Neurologically active compounds and compounds with multiple activities

ABSTRACT

This invention provides pharmacologically active compounds having neurological and other bio-active capability. These active compounds comprise the derivatives of guanidino, aminoguanidino, 2-imadazolino, 2-hydrazinoimidazolino or 2-guanidinobenzimidazolino groups.

This application is a continuation of application Ser. No. 09/377,878,filed Aug. 19, 1999, now U.S. Pat. No. 6,413,962, which is acontinuation of application Ser. No. 08/147,150, filed Nov. 2, 1993, nowabandoned, which in turn is a continuation of copending application Ser.No. 07/956,600, filed Oct. 5, 1992, which in turn is acontinuation-in-part of copending application Ser. No. 07/189,464, filedMay 2, 1988.

This invention relates to a group of receptor active compounds,primarily adrenergically active, and more particularly to compounds thatcontain a guanidino group or an amidino group.

It has previously been recognized that a variety of guanidinederivatives have alpha-adrenergic receptor activity in vivo. A varietyof guanidine derivatives have also been used clinically asanti-hypertensive agents, including clonidine, guanabenz, guanacline,guanadrel, guanazodine, guanethidine, guanfacine and guanochlor,guanoxabenz and guanoxan.

There has recently been interest in the treatment of severe spinaltrauma. The treatment has resulted in reduction of the ensuingspasticity in human, and in many spinal cord injured mammals. It hasalso resulted in partial or complete recovery of sensory-motor controlbelow the trauma level. Publications by the present inventor and byothers, confirming by independent tests the inventor's results with theuse of clonidine, a known alpha₂-adrenoceptor agonist, include, forexample: “Functional Restoration of the Traumatically Injured SpinalCord in Cats by Clonidine”, Naftchi, N. E., SCIENCE 217, pages 1042–1044(1982); THE PHYSIOLOGIST, Volume 27, page 220, August, 1984,“Histochemical Correlates Of Behavioral Effect of Alpha-2 AdrenergicAgonist in Spinal Rats”, N. E. Naftchi, et al, and a more complete textprovided in a paper given at the American Congress For RehabilitationMedicine, 61st Annual Session, Oct. 23, 1984, “Newer Research in SpinalCord Injury, Mechanism and Prevention of Acute Spinal Cord Injury”“Treatment of Mammalian Spinal Cord Injury With Antioxidants”, by N.Eric Naftchi, INT. J. DEVL. NEUROSCIENCE, vol. 9, No. 2, pp 113–126(1991).

Clonidine and guanabenz, both alpha₂-adrenergic receptor agonists usedin the earlier work, had limited usefulness because long-term treatmentwith these two agents resulted in the sedation, sleepiness anddesensitization of the subjects. In addition to these side effects,these agents also cause hypotension and syncopy, which tend to reducemobility and thus delay rehabilitation and recovery of the spinal cordinjured subjects. Further other side effects include constipation andrectal impaction which in tetraplegic subjects and paraplegic subjectswith lesions above thoracic sixth vertebrae can paradoxically result insevere hypertension, a syndrome known as autonomic hyperreflexia.

This application further relates to new anesthetic and hypothermicagents, and more particularly to the use as general anesthetic and/orhypothermic agents, in mammals, of a previously known pharmacologiccompound, guanabenz and certain of its related compounds (“guanidinocompounds”). When both properties, anesthesia and hypothermia are foundin the same compound, its administration results in pseudo-hibernation,that results in a relatively bloodless operating field, which can bebeneficial when undergoing major surgery. These guanidino compounds alsohave other valuable pharmocologic properties.

Guanabenz has long been used in clinical pharmacology, generally by oraladministration, as an antihypertensive agent. It is known to be astimulant, or agonist, of central alpha₂-adrenergic receptors, resultingin a decrease of sympathetic outflow from the brain at the bulbar levelto the peripheral circulatory system.

Among the known “adverse effects” of guanabenz as an antihypertensiveagent are sedation, anxiety, ataxia, depression, and sleep disturbances.Although most prior clinical use of guanabenz has involved oraladministration, earlier parenteral testing in dogs had producednatriuresis, thus contraindicating long-term administration by thisroute for hypertension treatment.

Accidental oral overdosages of guanabenz, have not been reported toresult in anesthesia; the incidents were recorded as hypotension,somnolence, lethargy, irritability, myosis and bradycardia in youngchildren.

In U.S. Pat. No. 4,060,640, Kodama et al., described guanabenz, and itsrelated compounds, as being central nervous system depressants thatreduced hyperexcitability and induced sedation, thus overcoming psychicdepression.

This alpha-adrenoceptor agonist has been shown to have a restorativeeffect on the central nervous system, especially in the treatment ofmotor and sensory functional losses due to the traumatic injury to thespinal cord (see U.S. Pat. No. 4,742,054).

GENERAL DESCRIPTION OF THE INVENTION

I. Sensory-Motor Function Restoration

It is an object of the present invention to provide novel compoundswhich have the capability of restoring to a mammal maximal sensory-motorfunction following damage to the central nervous system caused by traumaor disease. It is a further object of the present invention to providenovel compounds having such capability but without undesirable sideeffects which would interfere with the treatment of any mammal havingsuffered traumatic central nervous system injury.

A further objective of the invention, the novel compounds areefficacious anti-spastic, or spasmolytic, agents that control spasticitycaused as a result of neurological damage. These drugs would alsoproduce little or no sedation or somnolence and would not drasticallylower blood pressure.

II. Anesthesia and Hypothermia

Guanidino compounds, among the alpha-adrenergic receptor agonists, arecapable of inducing profound anaesthesia and/or hypothermia in mammals,when administered in a sufficient unit dosage, i.e., at least about 3mg/kg in rats and 0.05 mg/kg in primates. In order to expedite andrender more efficient the onset of anesthesia, guanabenz is preferablyadministered intraperitoneally (I.P.), or intravenously (I.V.), in theusual liquid vehicles, e.g., preferably a 5% aqueous dextrose solution.The guanidino compound can be provided in any of the usualpharmaceutical forms, e.g., as a physiologically acceptable salt, suchas guanabenz acetate, guanabenz HCl, guanabenz maleate, or guanabenzsodium succinate, dissolved in, e.g. a 5% aqueous dextrose solution. Asguanabenz and others of these guanidino compounds are capable of passingthrough the blood-brain barrier, unlike many non-volatile anesthetics,they need not be administered intrathecally.

The term “guanidino compounds” for both groups of activities includesany compound which has adrenergic receptor activity and which issufficiently lipophilic to I.

pass the blood-brain barrier in the central nervous system; and whichinclude the moiety:

-   in which “n” can be an integer from 1 to 3. The above moiety can be    a branched acyclic group as shown above, or the atoms “C”, N^(a),    “N^(b)” or “N^(c)” can be part of a cyclic group, for example, an    imidazolino, a benzimidazolino, a melamine (or triazine) group, an    amino-1,3-diazacyclopentene-(2), aminocaffeine, an    amino-1,3-diazacyclohexene-(2), or 3,5-Diamino-1,2,4-triazole.

This guanidino moiety can be part of a xanthine group, such as in8-aminocaffeine, or a separate group linked with a xanthine group, suchas by reacting a guanidino compound with theophylline-7-acetic acid,which product possesses alpha and beta adrenergic activity. When themoiety is combined with, i.e., 5-OH-tryptamine-3,4-dihydroxyacetaldhyde,gamma-aminobutyric acid, or choline, the resulting compound, in additionto alpha adrenoceptor activity, possesses serotonergic, dopaminergic,GABA-ergic, or cholinergic activities, respectively.

In the guanidino group of Formula I, above one of N^(a), N^(b) or N^(c)can be replaced with a sulfur or oxygen atom, i.e., —S—, or —O—, andalso obtain the desired agonist activity. When one of N^(a), N^(b) orN^(c) is replaced by a carbon atom (—C—), the resulting compoundcontaining the group has an alpha-adrenergic antagonist activity, e.g.,will reverse hypothermia or anesthesia induced by guanabenz, such asexemplified by compounds Nos. 96–101, 162, 163, 192, in Table I, below.These adrenergic antagonist compounds are also neuroprotective and,similar to guanidino compounds, possess glutamate (NMDA) receptorantagonistic activities.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the first aspect of the present invention, there areprovided pharmacologically active compounds having the capability ofreestablishing previously nonfunctioning or dysfunctioning, or destroyedneurological functions in a traumatized or diseased mammal. Thesecompounds comprise the reaction products of a guanidino, aminoguanidino,2-imidazolino, 2-hydrazinoimidazolino, 2-guanidinobenzimidazolino,3,5-diamino-1,2,4-triazole and the like groups with a methylatedxanthine group, which provide a combination of receptor activitydesigned to stimulate appropriate receptors in the brain and spinal cordand thereby reestablish the lost negative feedback and thereby tonicallystimulate sensory and motor neurons, in spite of a severely damagedcentral nervous system. These compounds are highly lipophilic and thuscapable of crossing the blood/CNS barrier and they preferably have thefollowing general formula:

A.

Wherein g and r can have a value of 0 or 1, to a total of one, h can be0, 1 or 2, and n is 0 or an integer of at least 1 and preferably notgreater than 2; the R groups can be hydrogen or non-interfering organicgroups. R₁ and R₂ and R₃ preferably include alkyl groups or hydrogenatoms, at least one of R₁ and R₂ and/or R₃ most preferably comprising analkyl group. R₁ and/or R₃ can be the bridging group to the guanidinomoiety outside of the brackets, and can be an aliphatic group, saturatedor unsaturated, preferably including a carboxyl group or a carbonylgroup, oxygen, nitrogen, sulfur, connected to a nitrogen atom of theguanidino group by a double bond. Thus R₁ and R₃ can preferably includeacetyl, acetaldehyde, propionyl, hydroxyalkyl. R₄ and R₅ can each behydrogen, or any non-interfering organic group, preferably includinglower alkyl, alkoxy, thioalkyl, alkenyl, aryl, aralkyl, or alkaryl or anucleoside group, or any such group substituted with NH₂, OH, OCH₃, orhalogen, sulfur, oxygen, or NO₂. R₆, if present, is a bridging groupforming a closed heterocyclic ring compound with the two nitrogen atomson the guanidino group, and can be any non-interfering organic group,which can include additional nitrogen atoms, halogen atoms, oxygenatoms, and can be aliphatic, cycloaliphatic, or aromatic, so as to formgroups such as, e.g., imidazole, benzimidazole, triazine,thiopyrimidine, triazolethiol, diphenyl-2-imidazole-thiol.

The novel compounds of the present invention have an alpha₂-adrenergicreceptor agonist moiety and a beta-adrenoceptor agonist moiety.Preferably, the beta-receptor agonist moiety (within the brackets) isderived from a compound that has an indirect beta-adrenergic effect,such as the substituted xanthines, which enhance the metabolic effect ofcyclic adenosine 3′,5′-monophosphate (c-AMP), by blocking c-AMPphosphodiesterase. These xanthines further enhance microcirculationwithin the muscle mass by increasing local vasodilation.

The present invention builds upon the effects noted in the earliestparent application hereto by combining in a single compound or complexthe effects of the alpha₂ and beta agonists.

As was noted during the earlier work, the previously knownalpha₂-adrenergic receptor agonists (“alpha₂-agonists”), have otherdirect physiological effects on the mammal being treated, which oftenare contraindicated following trauma, such as spinal injury, e.g., thehypotensive effect of clonidine and guanabenz. It was recognized thatsuch undesirable side effects can be counteracted by the simultaneous orsequential administration of an antagonist or a pressor agent, such asangiotensin II which could be titrated against the alpha₂-agonist.Usually, it was extremely difficult to avoid any such hypotensiveeffect, or some time serious hypertensive effects. The compounds of thepresent invention, which include the guanidino, 2-amino-imidazolino,2-hydrazino-imidazolino, 2-guanidinobenz-imidazolino,3,5-Diamino-1,2,4-triazolino, or 2,3,5-s-triazine moiety, as the alpha₂agonist, plus a beta-agonist moiety, avoid severe hypotensive effect,and result in an improved reactivation and reestablishment of thedescending monoaminergic pathways and ascending nociceptive pathwayswhile also improving upon and speeding up the affirmative process ofrestoring motor and sensory functions to almost one/third of the timerequired by the alpha₂ agonists.

The indirect beta-agonists, such as substituted xanthines, act byinhibiting the enzyme c-AMP phosphodiesterase, with the effect ofincreasing the ratio of c-AMP to c-GMP (cyclicguanosine-3′,5′-monophosphate). In addition, moieties derived fromdirect acting beta-agonist, such as 4-hydroxy-3-methoxymandelic acid,3,4-dihydroxymandelic aldehyde, 3,4-dihydroxyphenyl(betahydroxy)-acetaldehyde may be combined through their aldehyde orcarboxyl groups with guanidine, aminoguanidine, etc. to yield internallyneutralized compounds which have similar effect.

Referring to Formula 1, the xanthine group is connected to the guanidinogroup through one of the guanidino-nitrogen atoms.

In addition, it has been found that similar effects can be obtained whenin the guanidino moiety, one of the nitrogen atoms in the guanidinogroup shown in Formula 1 is replaced by a sulphur or an oxygen atom.

Typical species of this class of mixed agonist compounds are set out inthe working examples below, as well by the following list:

-   A1. Guanidino-7-Acetyltheophylline-   A2. 2-Guanidinobenzimidazolyl-7-Acetyltheophylline-   A3. 3,4,5-Trimethoxybenzylidene-2-Hydrazinoimidazole-   A4. 2-Hydrazinoimidazolyl-7-Acetyltheophylline-   A5. Theobromine-1-Acetyl Guanidine-   A6. Theophylline-7-Acetylamidoguanidine-   A7. Theobromine-1-Acetylamidoguanidine-   A8. Theophylline-7-Acetyliminoguanidine-   A9. 2,4,6-Tris(7-Acetamidotheophylline)-1,3,5-s-Triazine-   A10.    2,4-Bis(2,6-Dicholorbenzylideneilnino)-6-(7-Acetamidotheophylline)-1,3,5-s-Triazine-   A11. 2,4-Bis    (1-Naphthylacetamido)-6(7-Acetamidotheophylline)-1,3,5-s-Triazine-   A12.    2,4-Bis(7-Acetamidotheophylline)-6-(2,6-Dichlorobenzyl-ideneamino)-1,3,5-s-Triazine-   A13. Theophylline-7-Ethyleneiminoguanidine

Other such mixed agonist compounds are exemplified by the 8-aminocaffeine compounds, such as cafaminol, or compounds numbered 191, 197,203, 205, 209, 213–215 in Table II, below. In such compounds, theguanidino group, in part, is formed as part of the xanthine group bysubstituting an amino group onto the eighth position of the xanthinegroup. One method of preparing these compounds is shown in U.S. Pat. No.3,094,531.

With mixed agonist or agonist-antagonist properties, the compounds ofthe present invention can be used as medicaments for mammals in the formof pharmaceutical preparations suitable for administration orally,parenterally, intraperitoneally, intravenously or as nasal spray. Thesecompounds can be administered in a substantially pure form, with otheractive ingredients which may be desirable, or merely with a suitablepharmaceutical vehicle. The compounds are generally crystalline solidswhich may be at least partially soluble in commonly used organic salts.They are also generally soluble in liquid pharmaceutical vehicles,including water. Generally, the compounds can be formed asphysiologically acceptable salts including the salts of inorganic acids,such as hydrochloric, hydriodic, sulfuric or phosphoric, as well asorganic acids including acetic, malic, ethionic, malonic, citric,benzoic and pamoic. Generally, these acid addition salts are moresoluble in water than the compounds per Se. Formulation in apharmaceutical vehicle can be carried out in accordance with techniquesand in vehicles which are wholly conventional to those skilled in theart for the intended mode of administration.

For example, preparations for oral administration can be in eitherliquid or solid form, including for example syrups, elixirs, powders,capsules or tablets. The materials are preferably prepared for unitdosage form as powders which are preferably pressed into tablets orsuitably encapsulated in, for example, conventional gelatine capsules.Any powders or compressed tablets can generally also comprise theusually suitable excipients and/or diluents, such as starch, lactose,stearic acid, magnesium stearate, dextrin or polyvinylpyrrolidone.

Other suitable solid carriers include magnesium stearate, sicarylalcohol, talc, vegetable oils or fats, alcohols such an benzyl alcohols,gums, waxes, alkylene or polyalkylene glycols, such as propylene glycolor polypropylene glycol and any other well known carriers.

Suitable sterile solutions or suspensions can be prepared for parenteralor intraperitoneal administration, e.g., intravenous, containing forexample water, physiological saline, benzyl alcohol, ethyl oleate,methylcellulose, dimethyl sulfoxide, polyethylene glycol liquid, as wellas other liquid excipients well known in the pharmaceutical orveterinary art. Other auxiliary pharmaceutical materials which can bepresent include preservatives, stabilizers, wetting or emulsifyingagents, or osmotic salts or buffering agents, as is well known to thepharmaceutical or veterinary art. As these formulations are generallywell known and conventional, more specific instructions need not bepresented for purposes of defining this invention.

As stated, the mixed alpha/beta receptor active compounds of the presentinvention are most effective in treating the undesirable after-effectsof traumatic spinal injury, including even transection of spinal cord.Restoration of at least some normal sensory and motor control can beobtained as a result of treatment, especially if carried out within arelatively short time after injury to the spinal cord.

Because the compounds of the present invention do not have many of theundesirable side effects of utilizing the prior alpha₂-adrenoreceptoragonists of the parent application, it is not necessary to postponetreatment using these novel compounds until after stabilization of thevital signs and recovery from the initial shock. Indeed, many of thesecompounds are also effective in treating the initial shock conditions byway of stabilizing or even slightly elevating arterial blood pressureand improving microprofusion pressure in the area of injury. Thus, thecompounds of the present invention have positive hemodynamic effect aswell as positive neurological effects.

In all cases, as explained in the earlier work, it is necessary toinsure, by taking active surgical steps, if necessary, to remove anymechanical obstruction and compression pressure as created by crushedbone, growth of scar tissue or connective tissue or any other mechanicalcause, especially in chronic spinal cord injured mammals.

The mixed agonists of this invention also have been found to interferewith the formation of undesirable scar tissue at the trauma site. It isbelieved that these mixed agonists interfere with triple helix formationin the synthesis of collagen protein, thus preventing or reducing theformation of hard scar tissue at the trauma site.

During treatment using the compounds of the present invention, it isgreatly preferred that the plasma level of the compound in the bloodstream of the mammal being treated be maintained as constant asfeasible. This is especially important with respect to spinal injuriesin order to reduce or substantially eliminate autonomic dysreflexia andspasticity during treatment until permanent return of sensory and motorfunction has been obtained. These compounds generally should beadministered in a proportion of at least about 10 mcg/kg of body weight,and preferably in an amount of at least 15 mcg and preferably not morethan about 100 mcg/kg of body weight, and most preferably not more thanabout 70 mcg/kg of body weight. However, it has been found that theoptimal proportion in the blood is not directly proportional to bodyweight, but rather to a combination of factors including body weight andbody superficial area.

It may be preferable to administer these novel pharmacological agentsusing a sustained release form, for example, the conventionallyavailable sustained release capsules or sustained release transdermalproducts. Alternatively, if it is not feasible to utilize the sustainedrelease forms, these novel compounds can be administered regularly atrelatively short intervals, for example, 2 to 4 times per day. Althoughnot as desirable for chronic long-term treatment, these compounds can,at least initially after the trauma, be administered intraperitoneallyor intravenously to maintain a constant, tonic effect by slowadministration of medication, or as a single injection, at intervals.

An additional effect of the present novel compounds, especiallyimportant in the immediate aftermath of traumatic injury and shock, isthe immediate stimulation of spinal cord motor neurons, which keeps themuscle mass from wasting, preventing loss of weight and demineralizationof the skeleton, all of which are common occurrences after spinal cordtrauma. In addition, by avoiding constipation, as is often caused bypure alpha₂ agonists, extreme hypertension and autonomic hyperreflexiaare also avoided. Further, since the compounds are relatively internallyneutralized with respect to c-AMP and c-GMP, receptor supersensitivitywill be greatly minimized.

Most of the novel compounds of the present invention in accordance withFormula IA above, can be prepared by reacting a first compound (“A”)which contains a guanidino group and which can be present as part of aheterocyclic group, e.g., an amino triazine group, an aminoarylimidazole, an amino benzylimidazole, or an aminoimidazoline group,or an equivalent thio compound where one of the nitrogen atoms formingany of the above groups is replaced by a sulphur atom, with a secondcompound (“B”) comprising a direct or indirect beta-adrenergic receptoragonist, such as a substituted xanthine or analogs of beta-hydroxyphenylacetic acid, aldehyde or amine. Each of the above A and B compoundspreferably include one of a carbonyl group (such as a carboxyl group oran aldehyde group), a hydroxyl group or an amino (—NH₂), which aremutually reactive. Most preferably, the “A” compound reacts through aprimary or secondary amino nitrogen atom forming part of the guanidinoor aminoguanidino moiety.

Suitable group A compounds include guanidine, aminoguanidine,2-guanidinobenz imidazole, 2-aminoimidazole, 2-aminodihydrothiazine,2-hydrazinoimidazoline, 2,4,6-triamino-1,3,5-s-triazine,2,4-diamino-6-phenyl-1,3,5-s-triazine,2,4-bis(diethylamino)-6-hydrazino-1,3,5-s-triazine,4-methyl-4H-1,2,4-triazole-3-thiole, 4,5,diphenyl-2-imidazole-thiole,2-(4-aminophenyl-6-methyl-benzothiazole), 3,5-diamino-1,2,4-triazole,8-aminocaffeine and their acid addition salts. The 8-aminocaffeinecompound can be prepared, e.g., by reacting 8-chlorocaffeine withammonia.

Useful B group compounds which are preferably direct or indirectbeta-agonists, can be, for example, theophylline, etofylline,theophylline-7-acetic acid, theophylline-7-acetaldehyde,7-(2,3-dihydroxy)-propyltheophylline, 1-theobromine acetic acid,1-theobromine acetaldehyde. Alternatively, 8-chlorocaffeine can bereacted with compounds having a free amino-group, to form the third legof the guanidino group, or to form a biguanide by reacting8-chlorocaffeine with, e.g., aminoguanidine, or 2-hydrazinoimidazole.

The following examples provide common procedures for preparing specieswhich are preferred for their activity with respect to the treatment ofdamage to the central nervous system, utilizing the group of reactantsto obtain final products containing both alpha- and beta-adrenergicactivity, in accordance with one aspect constituting the presentinventions. These procedures are similar to methods commonly used in thepreparation of complex organic chemicals. These illustrative compoundswithin the present invention may, of course, also be prepared by otherpaths.

In each example, the final product is designated by a capital letter, toprovide a shorthand identification for the compound in subsequentportions of this text.

EXAMPLE 1 Preparation of Guanidino-7-Acetyltheophylline (C)

Theophylline-7-acetic acid (TAA) (0.42 moles, 100 grams) is admixed withexcess thionyl chloride (SOC12) and slowly heated to 45° C. and refluxedfor 2 hours. When reaction is completed, the excess SOC12 is removedunder vacuum evaporation at 50° C., in the presence of benzene (80grams). The vacuum evaporation with benzene is repeated three times toeliminate all residual SOC12. The resultant compound,theophylline-7-acetyl chloride (“TAC”) is added to a solution ofguanidine hydrochloride (0.25 mols, 60 grams) and 5 equivalents of 2normal sodium hydroxide at 0° C.

The mixture is stirred vigorously for thirty (30) minutes until aprecipitate is completely formed. The resultant yellow precipitate isfiltered out by Whatman No. 1 filter paper; the filtered solid isadmixed with water and the pH reduced to 8 by the addition of HCl. Theaqueous solution is again vacuum evaporated at 25° C., and the resultantdry yellow solid is dissolved in an alcohol solution of 80% ethanol andwater and recrystalized.

The resultant product has a molecular weight of 280.26 and has theformula shown in Table IIA.

TABLE IA COM- MOLAR POUND RATIO ABBREV. A B A:B PRODUCT 1. C GUANIDINE.HCl THEOPHYLLINE-7-ACETIC 1:1 GUANIDINO-7-ACETYLTHEOPHYLLINE ACID 2. D2-GUANIDINOBENZ THEOPHYLLINE-7-ACETIC 1:1 2-GUANIDINOBENZIMIDAZOLYL-7-IMIDAZOLE ACID ACETYLTHEOPHYLLINE 3. E 2- THEOPHYLLINE-7-ACETIC 1:12-HYDRAZINOIMIDAZOYL-7- HYDRAZINOIMIDAZOLINE, ACID ACETYLTHEOPHYLLINEHBR 4. F GUANIDINE 1-THEOBROMINEACETIC ACID 1:1 THEOBROMINE-1-ACETYLGUANIDINE 5. C₂ AMINOGUANIDINE THEOPHYLLINE-7-ACETIC 1:1THEOPHYLLINE-7-ACETYLAMIDO- ACID GUANIDINE 6. G AMINOGUANIDINE1-THEOBROMINEACETIC ACID 1:1 THEOBROMINE-1-ACETYLAMIDO- GUANIDINE 7. NAMINOGUANIDINE THEOPHYLLINE-7- 1:1 THEOPHYLLINE-7-ETHYLENEIMINO-ACETALDEHYDE GUANIDINE 8. C4 GUANIDINE THEOPHYLLINE-7- 1:1THEOPHYLLINE-7-ETHYLENE- ACETALDEHYDE GUANIDINE 9. GUANIDINO-ACETIC ACID7-(2,3-DIHYDROXY) PROPYL 2:1 7-(2,3-DIGUANIDINOACETATE) THEOPHYLLINEPROPYLTHEOPHYLLINE 10. H 2,4,6-TRIAMINO-s-TRIAZINE THEOPHYLLINE-7-ACETIC1:3 2,4,6-TRIS (7- ACID ACETAMIDOTHEOPHYLLINE)-1,3,4- s-TRIAZINE 11. J2,4,6-TRIAMINO-s-TRIAZINE 2,6-DICHLOROBENZALDEHYDE + 1:2:1 2,4-BIS (2,6-THEOPHYLLINE-7-ACETIC DICHLOROBENZYLIDENEIMINO)-6- ACID(7-ACETAMIDOTHEOPHYLLINE)- 1,3,5-s-TRIAZINE 12. K2,4,6-TRIAMINO-s-TRIAZINE 1-NAPHTHYLACETIC ACID + 1:2:1 2,4-BIS(1-NAPHTHYLACETAMIDO)-6- THEOPHYLLINE-7-ACETIC(7-ACETAMIDOTHEOPHYLLINE)- ACID 1,3,4-s-TRIAZINE 13. L2,4,6-TRIAMINO-s-TRIAZINE 2,6-DICHLOROBENZALDEHYDE + 1:1:2 2,4-BIS (7-THEOPHYLLINE-7-ACETIC ACETAMIDOTHEOPHYLLINE)-6-(2,6- ACIDDICHLOROBENZYLIDENEAMINO)- 1,3,5-s-TRIAZINE 14.2,4,6-TRIAMINO-s-TRIAZINE THEOPHYLLINE-7-ACETIC 1:1:12-(7-ACETAMIDOTHEOPHYLLINE)-4- ACID 1-THEOBROMINEACETIC(1-ACETAMIDOTHEOBROMINE)-6- ACID AMINO-1,3,4-s-TRIAZINE 15.4,5-DIPHENYL-2- THEOPHYLLINE-7-ACETIC 1:1 THEOPHYLLINE-7-ACETYL-2-(4,5,-IMIDAZOLETHIOLE ACID DIPHENYL)-2-THIOMIDAZOLE 16. 2-(4-AMINOPHENYL)-6-1-THEOBROMINEACETIC ACID 1:1 1-THEOBROMINEACETYL-2-(4-METHYL-BENZOTHIAZOLE AMINOPHENYL)-6- METHYLBENZOTHIAZOLE

TABLE IIA 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14

EXAMPLE 2 Preparation 2-(Theophylline-7-acetamido)-2-iminobenzimidazole(Compound D)

The acylchloride of TAA is obtained by following the same procedure inEXAMPLE 1 above. The TAC (100 g.) is then added dropwise to a solutionof 2-guanidino-benzimidazole(GBI) (74 grams) in a mixture of benzene andpyridine (which is active both as a catalyst and to neutralize theby-product hydrogen chloride).

The reacting mixture is held overnight at room temperature (21° C.); thebenzene layer is then separated by decanting and washed with an aqueoussolution of 2 Normal HCl (to remove any excess pyridine), subsequentlywashed with an aqueous solution of 2 Normal sodium hydroxide, and washedagain with pure deionized water, until reaching neutral pH (pH 6.8–7.2).

The benzene solution is then dried under vacuum (at 25° C.) and theresultant solid is dissolved and recrystalized from an aqueous solutionof 80% ethanol. The product has a molecular weight of 394.4 and has theformula shown in Table IIA, above.

EXAMPLES 3–14

Additional Preparations

Following the same procedures as in Examples 1 and 2, additionalcompounds can be prepared by reacting the reagents to form the compoundsas indicated in Table IA, above.

Biological Activity

The novel compounds of the present invention have been tested and foundto be extremely effective in treating severe neurological disorders orthe type resulting from either severe traumatic injury to the spinalcord or from systemic diseases such as multiple sclerosis. Thesecompounds are believed to act upon receptors at several sites. Thestimulating of the receptors in the spinal cord, either directly orindirectly, tonically stimulates the motor neurons, thus preservingmuscle mass. These drugs generally have long-term ameliorative effects,which apparently bring about a reorganization within the nervous system,providing for regaining of central nervous system control over lostfunctions in those portions of the body distal to the brain and belowthe damaged spinal cord site. These compounds reduce spasticity andtheir chronic use results in control over distal body functions, forexample, over the activity of the urinary tract or the legs. Alsosignificantly, the desirable results are obtained without sedating orlowering the blood pressure of the mammal.

In the following examples, specific methods of administration aredescribed. However, unless otherwise stated, similar response can beelicited by following other means of administration.

COMPARATIVE EXAMPLE A

A cat was anesthetized using intravenous pentobarbital (30 mg/kg) afterwhich its arterial blood pressure was continuously monitored for atleast two hours. After recording stable arterial blood pressure, adorsal laminectomy was performed in the thoracic region of the cat fromT3 to T5; after restoration of blood pressure, the cat was traumatizedby means of a twenty gram weight being dropped from a height oftwenty-five centimeters (500 g-cm force) on the exposed dura of thespinal cord at the fourth thoracic segment.

The cat was not thereafter treated except to surgically clean the traumaregion and assist in the healing of the surgery.

The cat was regularly observed over a four month period.

Somatosensory-evoked potentials (SEPs) were measured and recorded forthis cat, immediately before the spinal trauma, 10, 20 and 30 minutesafter the trauma, and two hours after the trauma, and then again 30 daysafter the trauma. The SEPs were generated by stimulating the sciaticnerve by means of needle electrodes inserted through the posteriorthighs. It is known that the recording of SEPs from the somatosensorycortex by stimulating lower extremities requires the presence of intactascending pathways. The absence of SEPs indicates a complete disruptionof the spinal cord tracks. Beginning 10 minutes after impact, the SEPwas substantially completely absent from the injured cat.

The cat did not regain the use of its lower extremities, nor did it everregain bladder and bowel control. The animal progressed from acute,flaccid phase to chronic, spastic and autonomically dysreflexic phase ofparalysis.

COMPARATIVE EXAMPLE B

The spinal cord of a group of rats was completely transected. Aftersurgery, the rats were treated with guanabenz. A solution of 4.0milligrams per milliliter of 5% dextrose in water solution was prepared72 hours after the lesion, guanabenz (0.65 mg/kg; I.P.) was given twiceper day intraperitoneally.

Following each administration of the guanabenz rats became sedated forat least 2 to 4 hours. The rats presented with a condition of bloodyeyes and nose for a period of 2 to 5 days after the transection. Duringthe first two-weeks, proper plantar placement, weight bearing on thehind limbs and/or coordinated walking was not present. However, by thethird week of such treatment, proper plantar placement, weight bearingon the hind limbs and walking movements of the hind limbs coordinatedwith those of the front limbs were observed in a majority of the rats toa satisfactory degree. The rats, however, showed some, but notsignificant loss of muscle mass in their hind limbs.

WORKING EXAMPLE 1

In a further group of six rats the spinal cord was transected inaccordance with the above Comparative Examples. After surgery andcleaning and mechanical treatment of the wounds in the same fashion, anintraperitoneal injection of 7-(guanidino-acetyl-theophylline (“C”) wasadministered at a dose of 5.0 mg/kg 24 hours post surgery. Within a 7 to9 day period, the rats engaged in walking movements of the hind limbscoordinated with those of the front limbs and the hind limbs, includingproper plantar placement and full weight bearing on the hind limbs.

Within 36 hours after the spinal cord transection, i.e., only 12 hoursafter initial administration of Compound C, the initial bloody eyes andnose condition had abated. The muscle mass was not reduced significantlyand the animals regained reflex activities much faster than controlrats. During the entire course of treatment, the animals did not exhibitany signs of sedation or lethargy. Further the animals were alert andcontinued to eat in substantially normal quantities.

Starting 24 hours post-transection, immediately after eachintraperitoneal administration of Compound C, reflexes such as thetail-flick and cross-extension would return, within 12 minutes postinjection. This short-term strong response was observed for at least 1½hours after each injection and gradually diminished until subsequentreadministration of Compound C, guanphylline. Within 8 to 11 days theresponse became sustained, and was accompanied by long-term therapeuticrestoration of coordinated movements, plantar placements andweight-bearing by the hind limbs.

Three weeks after discontinuance of the treatment with Compound C, thecondition of the animal remained extremely stable and the animal clearlyhad greater control over his movements than those treated withguanabenz, whereas the control rats of Comparative Example A weresubstantially incapacitated.

None of these rats treated with Compound C developed any spasticitywithin six months of trial after the spinal cord transection.

Measurement of blood pressure in the cat and sheep showed a slightincrease immediately after administration of Compound C, which returnedto basal level within 10 minutes.

WORKING EXAMPLE 2

It was noted that some of the untreated rats in Comparative Example Adeveloped severe spasticity three weeks after transection. Treatment ofthree of these control rats with guanphylline (Compound C),intraperitoneally for 7 days, (4.0 mg/kg BID), resulted in a markeddecrease in spasticity within 4 days and a complete elimination after 7days. None of the rats initially treated with the Compound C developedspasticity at any time.

WORKING EXAMPLE 3

Ten cats were spinally traumatized in accordance with the procedure setforth above in Comparative Example A. Five of these spinal cats weretreated with Compound C commencing three hours after trauma and five ofthe cats were treated with guanabenz beginning at the same time. Thecats treated with guanabenz (0.65 mg/kg bid) exhibited tight urinarysphincter and dyssinergia during urodynamic examination four to fiveweeks after treatment began. Those cats treated with the same quantityof Compound C during the same period had substantially completelyrecovered urinary bladder function and exhibited little or nodyssinergia after only seven to twenty-one days of treatment.

Spinalized cats required eight weeks of treatment with guanabenz beforeregaining controlled micturition. Cats treated with Compound C, requiredonly three to five weeks of treatment to achieve the same results.

It is clear that the novel compounds of this invention are effective notonly for the smaller mammals, but also for larger mammals includingprimates.

When testing the other compounds listed in Table I above, in accordancewith the above procedures, substantially the same results are achieved.

Anesthetics and Hypothermics and Other Neuroprotective Compounds

The second group of guanidino compounds are compounds which haveneuroprotective efficacy, and in some cases are also effective asanesthetics and/or hypothermic agents, which have other desirableproperties, and which preferably have the following formulae:

Referring to Formulae II, n can be zero or an integer up to 2; Z, X1,X2, Y1 and Y2 can be the same or different and can include, as examples,hydrogen, halogen, trifluoromethyl or C1–C4 alkyl oxyalkyl, hydroxyl,phenyl or condensed phenyl, phenoxy, naphthoxy, or substituted such arylor aryloxy groups; preferably, one substituent is halogen ortrifluoromethyl, at least one of X1 and Y1 is not hydrogen and not morethan three of the X1, Y1, X2, Y2 and Z groups are other than hydrogen;each of R, R′, R″ and R* can be, for example, hydrogen, C1–C4 alkyl,C2–C4 alkenyl, or C2–C4 alkynyl, with the proviso, among otheralternatives, that any two of R*, R″ and R′ can together form ahydrocarbyl bridge of preferably from 2 to 4 carbon atoms, such asalkylene or alkenylene groups, and with the further proviso that one ofY1 and R is preferably hydrogen. The term “hydrocarbyl bridge of 2 to 4carbon atoms” is exemplified and illustrated by the following examples,the bracketed portions being the bridging groups:

In the guanidino compounds of Formulae II and III, X1 preferably ismiddle halogen—that is, chlorine or bromine, Y1 is also preferablymiddle halogen, Z preferably is hydrogen or middle halogen, and R, R′,R″ and R′ are preferably all hydrogen.

When N, in

in Formula II, is replaced by a carbon atom, i.e.,

in Formula II, the guanidino moiety is changed to an amidino group andthe compound becomes an alpha adrenoceptor antagonist, as in Compounds96–101, 162, 163, and 192 in Tables I and II below. They will thusantagonize hypothermia and anesthesia, and also have neuroprotectiveactivity, i.e., after trauma or disease caused by injury, to reducedamage to the central nervous system.

Referring to Formula III, X, Y and Z can be the same or differentgroups, which cumulatively confer sufficient lipophilicity to theoverall compound to permit passage through the blood-brain barrier, anddo not interfere with the alpha-adrenergic activity of the guanidinomoiety, shown set off by phantom lines.

Groups Y and Z can each be connected to the triazine group ringstructure by a nitrogen atom, and in such cases each group is thus thesame, or different, from the (N^(a)-X) group. It has thus been foundthat being part of the triazine group of Formula No. III, or of anothercyclic structure (including a xanthine group), does not eliminate theadrenoceptor activity of the guanidino moiety. The groups Y, Z and X,must be sufficiently lipophilic to allow the compound to pass throughthe blood-brain barrier, without hindering the adrenergic, dopaminergic,serotonergic, GABA-ergic or cholinergic agonist activity of theneighboring groups. The groups X, Y, and Z, can thus have some otherpharmacologic activity in addition to the alpha adrenergic agonistactivity.

These lipophilic groups can be aromatic, cyclic or acyclic, althougharomatic groups are generally preferred. Such lipophilic groups include,as examples, any “B group” shown above for the Formula II, guanidinocompounds, and can also include any of the receptor active groups ofsufficient cumulative lipophilicity, in any combination, shown in thecompounds of Tables I and II below.

The aromatic groups useful as substituents for these guanidino compoundspreferably include phenyl rings, either a single phenyl ring or two ormore phenyl rings, condensed or linked and preferably furthersubstituted with, e.g., one or more halogen atoms, especially chlorineor bromine, oxyalkyl groups, such as oxymethyl, hydroxy groups,hydroxyalkyl groups, and alkyl groups; the alkyl groups substituted onto the phenyl rings preferably have not more than about five carbonatoms, each.

Table I presents the structural formulae for an exemplary list of novelcompounds which are useful in the present invention. It should beunderstood that the listing set forth in Table I is purely exemplary andis in no way intended to be exhaustive.

TABLE I  (1)

 (2)

 (3)

 (4)

 (5)

 (6)

 (7)

 (8)

 (9)

 (10)

 (11)

 (12)

 (13)

 (14)

 (15)

 (16)

 (17)

 (18)

 (19)

 (20)

 (21)

 (22)

 (23)

 (24)

 (25)

 (26)

 (27)

 (28)

 (29)

 (30)

 (31)

 (32)

 (33)

 (34)

 (35)

 (36)

 (37)

 (38)

 (39)

 (40)

 (41)

 (42)

 (43)

 (44)

 (45)

 (46)

 (47)

 (48)

 (49)

 (50)

 (51)

 (52)

 (53)

 (54)

 (55)

 (56)

 (57)

 (58)

 (59)

 (60)

 (61)

 (62)

 (63)

 (64)

 (65)

 (66)

 (67)

 (68)

 (69)

 (70)

 (71)

 (72)

 (73)

 (74)

 (75)

 (76)

 (77)

 (78)

 (79)

 (80)

 (81)

 (82)

 (83)

 (84)

 (85)

 (86)

 (87)

 (88)

 (89)

 (90)

 (91)

 (92)

 (93)

 (94)

 (95)

 (96)

 (97)

 (98)

 (99)

(100)

(101)

(102)

(103)

(104)

(105)

(106)

(107)

(108)

(109)

(110)

(111)

(112)

(113)

(114)

(115)

(116)

(117)

(118)

(119)

(120)

(121)

(122)

(123)

(124)

(125)

(126)

(127)

(128)

(129)

(130)

(131)

(132)

(133)

(134)

(135)

(136)

(137)

(138)

(139)

(140)

(141)

(142)

(143)

(144)

(145)

(146)

(147)

(148)

(149)

(150)

(151)

(152)

(153)

(154)

(155)

(156)

(157)

(158)

(159)

(160)

(161)

(162)

(163)

(164)

(165)

(166)

(167)

(168)

(169)

(170)

(171)

(172)

(173)

(174)

(175)

(176)

(177)

(178)

(179)

(180)

(181)

(182)

(183)

(184)

(185)

(186)

(187)

(188)

(189)

(190)

(191)

(192)

(193)

(194)

(195)

(196)

(197)

(198)

(199)

(200)

(201)

(202)

(203)

(204)

(205)

(206)

(207)

(208)

(209)

(210)

(211)

(212)

(213)

(214)

(215)

(216)

(217) Chlorguanide Merck (11th Ed.) p. 2084 (218)

(219)

(220)

(221)

(222)

(223)

(224)

(225)

(226)

(227)

(228)

(229)

(230)

(231)

(232)

(233)

(234)

Table II presents the chemical reactants for the preparation of theexemplary novel compounds of this invention listed in Table I, beingnumbered in parallel to the numbering of Table I. The products in TablesI and II are prepared according to the method described for preparingsuch compounds in accordance with this invention.

TABLE II Reactants Product (1) 2,6-Dichlorobenzoic acid +2,6-Dichlorobenzamidoguanidine Aminoguanidine (2) 2,6-Dichlorobenzoicacid + 2-(2,6-Dichlorobenzamido)-2-amino- 2-Hydrazinoimidazole imidazole(3) 4-Methylbenzaldehyde (2 mols) + Bis-(4-methylbenzylidene)-guanidineGuanidine (4) 2,6-Dichlorobenzaldehyde (2 mols) +2,4-Bis-(2,6-dichlorobenzylideneamino)- 5-Hydroxyindole-3-acetaldehyde +6-(5-hydroxyindole-3-ethylamino)-1,3,5- Melamine s-triazine (5)5-Hydroxy-3-indole acetic acid + 2-(Amino)-4-(5-hydroxyindole-3-1-Naphthylacetic acid + acetamido)-6-(1-naphthylacetamido)- Melamine1,3,5-s-triazine (6) 2-Hydroxybenzoic acid2-(Guanidinoacetoxy)-1-methylbenzoic methyl ester + acid esterGuanidinoacetic acid (7) 2,6-Dichlorobenzaldehyde +2-(Amino)-4-(2,6-dichlorobenzyl- 3,4-Dihydroxymandelic aldehyde +ideneamino)-6-(3,4-dihydroxyphenyl- Melamine 7-(R) or7-(S)-hydroxyethyleneamino)- 1,3,5-s-Triazine (8)2,6-Dichlorobenzaldehyde (2 mols) +2,4-Bis-(2,6-dichlorobenzylideneamino)-3,4-Dihydroxyphenylacet-aldehyde +6-(3,4-dihydroxyphenylethylamino)-1,3,5- Melamine s-triazine (9)2-Acetoxybenzoic acid + 2-(Amino)-4-(2-acetoxybenzamido)-6-3,5-Dichlorophenylacetic acid + (3,5-dichlorophenylacetamido)-1,3,5-s-Melamine triazine (10) Aminoguanidine +2-Acetoxybenzylideneaminoguanidine 2-Acetoxybenzaldehyde (11)2,4-Dichlorophenoxybutyric acid + 2,4-DichlorophenoxybutyramidoamidineGuanidine (12) 4-Chlorobenzaldehyde(2 mols) +2-(Amino)-4,6-bis-(4-chlorobenzyl- Melamine ideneamino)-1,3,5-s-triazine(13) 3,4,5-Trimethoxybenz-aldehyde +2-(3,4,5-Trimethoxybenzylideneamino)-2- 2-Hydrazinoimidazoleaminoimidazole (14) 2,6-Dichlorobenzaldehyde +2-(Amino)-4-(4-aminobutyramido)-6- 4-Aminobutyric acid +(2,6-dichlorobenzylideneamino)-1,3,5-s- Melamine triazine (15)Phenylactic acid + 2-(Phenylacetamido)-2-aminoimidazole2-Hydrazinoimidazole (16) 2,6-Dichlorobenzaldehyde +2,6-(Dichlorobenzylideneamino)-amidine Guanidine (17)2,6-Dichlorobenzaldehyde(2 mols) +2-(Amino)-4-6-bis-(2,6-dichlorobenzyl- Melamineideneamino)-1,3,5-s-triazine (18) 2,6-Dichlorobenzylaldehyde(3 mols) +2,4,6-tris-(2,6-Dichlorobenzyl Melamine ideneamino)-1,3,5-s-triazine(19) 4-Hydroxy-3-methoxy- 2-(Amino)-4,6-bis-(4-hydroxy-3- phenylaceticacid(2 mols) + methoxyphenylacetamido)-1,3,5-s- Melamine triazine (20)1-Naphthaldehyde(3 mols) + 2,4,6-Tris-(1-naphthylmethyleneimino)-Melamine 1,3,5-s-triazine (21) 2,4-Diamino-6-phenyl-2,4-Bis-(2,6-dichlorobenzylideneamino)- 1,3,5-s-triazine(2 mols) +6(phenyl)-1,3,5-s-triazine 2,6-Dichlorobenzaldehyde(2 mols) (22)2,4-Dichlorophenoxy- 2-(Amino)-4,6-bis-(2,4-dichlorophenoxy- butyricAcid(2 mols) + butyramido)-1,3,5-s-triazine Melamine (23)2,6-Dichlorobenzaldehyde + 2-(Acetoxybenzamido)-4-(2,6-dichloro-Theophylline-7-acetic acid + benzylideneamino)-6-(theophylline-7-2-Acetoxybenzoic acid + acetamido)-1,3,5-s-triazine Melamine (24)3,4,5-Trimethoxybenz- 2-(Amino)-4,6-bis-(3,4,5-trimethoxy- aldehyde (2mols) + benzylideneamino)-1,3,5-s-triazine Melamine (25)2-(Hydrazino)-4,6-bis 2,4-Bis-(diethylamino)-6-(3,4,5-(diethylamino)-1,3,5-s- trimethoxybenzylidenehydrazino)- triazine +1,3,5-s-triazine 3,4,5-Trimethoxy- benzaldehyde (26)N-(4-Hydroxyphenyl)-acetamide + N-(4-Guanidinoacetoxy)-acetanilideGuanidinoacetic acid (27) Hydralazine + N-(Guanidinoacetamido)-1-amino-Guanidinoacetic acid phthalazine (28) 5-Hydroxytryptamine +N-(2,6-Dichlorobenzylidene)-5- 2,6-Dichlorobenzaldehyde +guanidinoacetoxy)-indole-3- Guanidinoacetic acid ethylamine (29)3,4-Dihydroxyphenyl 2-(2,6-Dichlorobenzylideneamino)-4- acetaldehyde +(3,4-dihydroxyphenylethylamino)-6- 5-Hydroxyindole-3-(5-hydroxyindole-3-ethylamino)- acetaldehyde + 1,3,5-s-triazine2,6-Dichlorobenzaldehyde + Melamine (30) 1-Naphthylacetic acid (3mols) + 2,4,6-Tris(1-naphthylacetamido)- Melamine 1,3,5-s-triazine (31)Betaine + 2-(Amino)-4-(1-carboxamido-N,N,N- Theophylline-7-acetic acid +trimethylmethaniminium)-6-(theophylline- Melamine7-acetamido)-1,3,5-s-triazine (32) Guanidinoacetic acid +Guanidinoacetylcholine HcL;1-(2-hydroxy- CholineN,N,N-trimethylethanaminium-1- guanidinoacetate ester (33)Guanidinoacetic acid + 1-Guanidinoacetoxy-3-methyl-1-butanol3-Methyl-1-butanol (34) Glycerol + 1,2,3-Propanetrioltriguanidinoacetate Guanidinoacetic acid (3 mols) ester;1,2,3-tris-(guanidinoacetoxy) propane (35) 2-Guanidinobenzimadazole +2-(Theophylline-7-acetamido)-2-amino- Theophylline-7-acetic acidbenzimidazole (36) Nicotinic acid + 2-Amino-4-(nicotinamido)-6-Theophylline-7-acetic acid + (theophylline-7-acetamido)-1,3,5-s-Melamine triazine (37) 5-Hydroxyindole-3-2-(5-Hydroxyindole-3-ethylamino)-2- acetaldehyde + amidinobenzimidazole2-Guanidinobenzimidazole (38) Aminoguanidine +5-Hydroxyindole-3-acetamidoguanidine 5-Hydroxyindole-3- acetic acid (39)6-Aminohexanoic acid + 2-(Amino)-4-(6-aminohexanamido)-6-Theophylline-7-acetic acid + theophylline-7-acetamido)-1,3,5-s- Melaminetriazine (40) 2-Acetoxybenzoic acid +2-(Amino)-4-(2-acetoxybenzamido)-6- Theophylline-7-acetic acid +(theophylline-7-acetamido)-1,3,5-s- Melamine triazine (41)Aminoguanidine + 2,4-(Dichlorophenoxybutyramido)- 2,4-Dichlorophenoxy-guanidine butyric acid (42) 2-Guanidinobenzimidazole +2-(2-Naphthoxyacetamido)-2-amidino- 2-Naphthoxyacetic acid benzimidazole(43) 2,6-Di-tert-butyl-4- 1-Guanidinoacetoxy-2,6-di-tert-butyl-4-methylphenol + methylphenol Guanidinoacetic acid (44)3,4-Dihydroxymandelic N-(2,6-Dichlorobenzylideneguanidino)-2- aldehyde +(3,4-dihydroxyphenyl)-2-(R) or-2-(S)- 2,6-Dichlorobenzaldhyde +hydroxyethylimine Aminoguanidine (45) 3,4-Dihydroxyphenyl-3,4-Dihydroxyphenylethylene acetaldehyde + aminoguanidine Aminoguanidine(46) 2-Aminobenzothiazole + 2-(2,6-Dichlorobenzylideneamino)-2,6-Dichlorobenzaldehyde benzothiazole (47) Melamine +2-(Amino)-4-(nicotinamido)-6-(3,4,5- Nicotinic acid +trimethoxyacetamido)-1,3,5-s-triazine 3,4,5-Trimethoxyphenyl- aceticacid (48) L-5-Hydroxytryptophan + 3-(5-Hydroxyindole)-2-(R)-or-2-(S)-2,6-Dichlorobenzaldehyde + (2,6-dichlorbenzylideneamino)-N-Aminoguanidine guanidinopropionamide (49) Guanidinoacetic acid +3-(guanidinoacetoxy)-3-methylpyridine Nicotinyl alcohol (50)L-3,4-Dihydroxyphenylalanine + 3-(3,4-Dihydroxyphenyl)-2-(R)-or-2-(S)-2,6-Dichlorobenzaldehyde + (2,6-dichlorbenzylideneamino)-N-Aminoguanidine guanidinopropionamide (51) Aminoguanidine +2,6-Dichlorophenylacetamidoguanidine 2,6-Dichlorophenylacetic acid (52)2-Hydrazinoimidazole + 2-(Indole-3-methylene)-2- Indole-3-carboxaldehydehydrazinoimidazole (53) Theobromine-1-acetic acid +Theobromine-1-acetamido-guanidine Aminoguanidine (54)1-Theobromineacetic acid + 2-(Amino)-4-(nicotinamido)-6- Nicotinicacid + (theobromine-1-acetamido)-1,3,5-s- Melamine triazine (55)4-Aminobutyric acid + 4-(Guanidinoacetamido)butyric acid Guanidinoaceticacid (56) 3,4-Dimethoxybenzoic acid +2-(Amino)-4-(2,6-dichloroacetamido)-6- 2,6-Dichloroacetic acid +(3,4-dimethoxybenzamido)-1,3,5-s- Melamine triazine (57)1-Theobromineacetic acid + 2-(Amino)-4-(2,6-dichlorophenyl-2,6-Dichlorophenylacetic acid + acetamido)-6-(theobromine-1-acetamido)-Melamine 1,3,5-s-triazine (58) Glycerol +1-(2,6-Dichlorophenylacetoxy)-3- Guanidinoacetic acid +(guanidinoacetoxy)-2-propanol 2,6-Dichlorophenylacetic acid (59)Glycerol + 1-(4-Aminobutoxy)-3-(guanidinoacetoxy)- Guanidinoaceticacid + 2-propanol 4-Aminobutyric acid (60) Adipic (hexanedioic) acid +1,4-Bis-(amidineamido)-butane Guanidine (61) Adipic acid +5-Guanidinamidopentanoic acid Aminoguanidine (62) Guanidineacetic acid +1,3-Dichloro-2-guanidinoacetoxypropane 1,3-Dichloro-2-propanol (63)Alpha tocopherol + 2,5,7,8-Tetramethyl-2-(4,8,12- Guanidineacetic acidtrimethyltridecyl)-6-guanidinoacetoxy chromanol (64)All-cis-5,8,11,14,17- All-cis-5,8,11,14,17- eicosapentaenic acideicosapentaenamidoguanidine (20:5, omega-3;EPA) + Aminoguanidine (65)3,4,5-Trimethoxyphenyl- 5-(3,4,5-Trimethoxyphenylacetoxy)- acetic acid +indole-3-ethyliminoguanidine 5-Hydroxyindole-3-acetaldehyde +Aminoguanidine (66) Melamine + 2,4,6-Tris-(3,4-dimethoxybenzylidene-3,4-Dimethoxycarbox- amino)-1,3,5-s-triazine aldehyde (3 mols) (67)2,6-Diisopropylaniline + N-(2,6-Diisopropylphenyl)- Guanidinoacetic acidguanidinoacetamide (68) 3,5-Dimethoxybenz- 2-(Amino)-4,6-bis(3,5-dimethoxybenzyl- aldehyde (2 mols) + ideneamino)-1,3,5-s-triazineMelamine (69) 2-(3,5-Dihydroxyphenyl)-2-(Amino)-4-(2,6-dichlorobenzylidene 2-hydroxyacetaldehyde +amino)-6-(3,5-dihydroxy-2-(R)-or-2-(S)- 2,6-Dichlorobenzaldehyde +hydroxyethylamino)1,3,5-s-triazine Melamine (70) Theophylline-7-aceticacid + 2-(2,6-Dichlorbenzylideneamino)-4-(3,5- 2,6-Dichlorbenzaldehyde +dihydroxy-2-(R)-or-(S)-ethylimino)-6- 3,5-Dihydroxymandelic-(theophylline-7-acetamido)-1,3,5-s- aldehyde + triazine Melamine (71)1-Naphthylacetic acid + 2-(Acetoxybenzamido)-4-(amino)-6-(1-2-Acetoxybenzoic acid + naphthylacetamido)-1,3,5-s-triazine Melamine(72) 3,5-Dichloroaniline + N-(3,5-Dichlorphenyl)-5-(guanidino-Guanidinoacetic acid + acetoxy)-indole-3-ethylamine 5-Hydroxyindole-3-acetic acid (73) 3,5-Dichloroaniline +N-(3,5-Dichlorphenyl)-N-guanidino- Guanidinoacetic acid acetamide (74)3,4,5-Trimethoxyphenyl- 5-(3,4,5-Trimethoxyphenylacetoxy)- acetic acid +tryptamine 5-Hydroxytryptamine (75) Aminoguanidine +3,5-Dihydroxy-2-(R)-or-(S)-ethyl- 3,5-Dihydroxy- iminoguanidine mandelicaldehyde (76) 3,5-Dihydroxymandelamine +2-(3,5-Dihydroxyphenyl-2-(R)-or-2-(S)- 2,6-Dichlorbenzaldehydehydroxyethylimino-N-(2,6- dichlorobenzylamine (77)3,4,5-Trimethoxyphenyl- 2-(3,4,5-Trimethoxyphenylacetoxy)- acetic acid +benzylideneaminoguanidine 2-Hydroxy benzylidine aminoguanidine (78)5-Hydroxytryptamine + N-(2,6-Dichlorbenzylidene)-3-(5-2,6-Dichlorobenzaldehyde hydroxyindole)ethylamine (79) 2-Hydroxybenzoicacid + 2-(Hydroxybenzamido)-guanidine Aminoguanidine (80)2-Hydroxybenzoic acid + 2-(Guanidinoacetoxybenzamido)-guanidineAminoguanidine + Guanidonoacetic acid (81) 2-Acetoxybenzoic acid +2-Acetoxybenzoylaminoguanidine Aminoguanidine (82)2-Hydroxybenzamidoguanidine + 2-(Theophylline-7-acetoxy)-Theophylline-7-acetic acid benzamidoguanidine (83) 2-Hydroxybenzoicacid + 2-(Theophylline-7-acetoxy)-benzoic acid Theophylline-7-aceticacid (84) 3,5-Dichloro-2-hydroxy-3,5-Dichloro-2-(theophylline-7-acetoxy)- benzylideneaminoguanidine +benzylidineaminoguanidine Theophylline-7-acetic acid (85) L-Histidine +2- N-(2-Aminoimidazolyl)-2-(R)-or-2-(S)- Hydrazinoimidazole +(2,6-dichlorobenzylideneamino)-4- 2,6-Dichlorobenzaldehydeimidazolylpropionamide (86) 2-Propylpentanoic acid +2-Propylpentanoylaminoguanidine Aminoguanidine (87) N2,N4,N6,Tris(hydroxymethyl) 2,4,6 Tris(3,4-dimethoxyphenylpropoxy melamine +methylamino)-1,3,5-s-triazine 3,4-Dimethoxyphenyl propionic acid) (3mols) (88) 4-Ethoxyaniline + 4-(4-Ethoxyphenyl)-guanidinoacetamideGuanidinoacetic Acid (89) 2-Hydroxybenzoylhydrazine +2-(Guanidinoacetoxy)-guanidino- Guanidinoacetic acid acetamidobenzamide(90) Aminoguanidine 6-Hydroxy-2,5,7,8-tetramethylchromanyl-6-Hydroxy-2,5,7,8- 2-carboxamidoguanidine tetramethylchroman-2-carboxylic acid (91) 2-Hydrazinopyridine +N-(2-Aminopyridyl)-2-(guanidinoacetoxy)- Salicylic acid + benzamideGuanidinoacetic acid (92) 2-Aminopyrimidine +2-(2,6-Dichlorobenzylideneamino)- 2,6-Dichorobenzaldehyde pyrimidine(93) 2-Amino-1,3,4-thiadiazole + 2-(3,5-Dichorophenylacetyl)-2-amino-3,5-Dichlorophenylacetic 1,3,4-thiadiazole acid (94)3-Amino-1,2,4-triazine + 3-(2,3,6,7-Tetrahydro-3,7-dimethyl-1-Theobromineacetic acid 2,6-dioxo-1 (2H) purineacetamido)-1,2,4-triazine (95) Aminoguanidine + 5-(Hydantoinacetamido)-guanidine5-Hydantoinacetic acid (96) 2-(Aminomethyl) benzimidazole +2-(Theophylline-7-acetamido)-2- Theophylline-7-acetic acidmethylbenzimidazole (97) Theophylline-7-acetic acid +4-(Amidino)-N-(theophylline-7-acetyl)- 4-Amidinobenzamide benzamide (98)2-Imidazole carboxaldehyde + 2-(3,4,5-trimeythoxyphenylaminomethyl)-3,4,5-Trimethoxyaniline imidazole (99) 4-Amidinobenzamide +4-(Amidino)-N-(2,6-dichlorophenylacetyl)- 2,6-Dichlorophenyl- benzamideacetic acid (100) 2-(Aminomethyl)benzimidazole +2-(3,4,5-Trimethoxybenzylidineamino)- 3,4,5-Trimethoxybenzaldehyde2-methylbenzimidazole (101) 2-Imidazolecarboxaldehyde +2-(2,6-Diisopropylanilino)-2- 2,6-Diisopropylaniline methyleneimidazole(102) Theophylline-7-acetic acid + 7-(3,5-Dichorophenylhydrazido)-7-3,5-Dichlorophenylhydrazine acetyltheophylline (103) Aminoguanidine +5-Methoxy-2-methyl-3- 5-Methoxy-2-methyl-3- indoleacetamidoguanidineindoleacetic acid (104) Guanidinoacetic acid +N-(4-Hydroxy-3-methoxybenzyl)- 4-Hydroxy-3-methoxybenzylamineguanidinoacetamide (105) All-cis-5,8,11,14,17- N-(All-cis-5,8,11,14,17-eicosapentaenoyl-aminoguanidine +eicosapentaenoylaminoamidino)-4-hydroxy- 4-Hydroxy-3-methoxyphenylacetic3-methoxyphenylacetamide acid (106) Guanidinoacetic acid(2 mols) +7-(2,3-Diguainidinoacetoxypropyl)- 7-(2,3-Dihydroxypropyl)- theophyllinetheophylline (107) Hydralazine + N-(3,4,5-Trimethoxybenzylideneguanidino3,4,5-Trimethoxybenzyl- acetyl)-1-hydrazinophthalazineidineguanidinoacetic acid (108) 3-(3,4-Dichorophenoxy)-3-(3,4-Dichorophenoxy)-benzylidene benzaldehyde + aminoguanidineAminoguanidine (109) 3,4-Dichorophenylacetaldehyde +3,4-Dichorophenylethylaminoguanidine Aminoguanidine (110)6-Hydroxy-2,5,7,8- 2,4,6-Tris-(6-hydroxy-2,5,7,8- tetramethylchroman-2-tetramethylchroman-2-carbonylmethyl carboxylic acid (3 mols) +amino)-1,3,5,s-triazine N2,N4,N6-Tris-(hydroxymethyl)- melamine (111)Guanidine + N,N′-Bis-(3,4,5-trimethoxybenzylidene) 3,4,5-Trimethoxy-guanidine benzaldehyde(2 mols) (112) 5-Methoxyindole-3-5-(Methoxy)-N-(3,4,5-trimethoxy- ethylamine + phenylacetyl)-tryptamine3,4,5-Trimethoxyphenyl- acetic acid (113) Guanidine +N,N′-Bis-(theophylline-7-acetyl)- Theophylline-7-acetic acid guanidine(114) Guanidine + N,N′-Bis-(6-hydroxy-2,5,7,8- 6-Hydroxy-2,5,7,8-tetramethylchroman-2-carbonyl)-guanidine tetramethylchroman-2-carboxylic acid (115) Aminoguanidine +N-(Guanidino)-3-(3,4,5-trimethoxy- 3,4,5-Trimethoxyphenyl-phenyl)-propionamide propionic acid (116)Theophylline-7-acetylguanidine +N-(6-Hydroxy-2,5,7,8-tetramethylchroman-6-Hydroxy-2,5,7,8-tetramethylchroman-2-carbonyl)-N′-(theophylline-7-acetyl)- 2-carboxylic acid guanidine(117) 6-Hydroxy-2,5,7,8- 6-(Guanidinoacetoxy)-2,5,7,8-tetramethylchroman-2- tetramethylchroman-2-carboxylic acid carboxylicacid + Guanidinoacetic acid (118) 5-Hydroxyindole-3-5-(6-Hydroxy-2,5,7,8-tetramethylchroman- ethylaminoguanidine +2-carbonyl)-5-hydroxyindole-3-ethyl- 6-Hydroxy-2,5,7,8- iminoguanidinetetramethylchroman-2- carboxylic acid (119) 6-Hydroxy-2,5,7,8-1-Guanidinoacetoxy-3-(6-hydroxy-2,5,7,8- tetramethylchroman-2-tetramethylchroman-2-carbonyl)-2- carboxylic acid + propanol1-Guanidinoacetoxy-2,3- propanediol (120) 2,4-Bis-(amino)-6-2-(4-Aminobutyramido)-4-(6-hydroxy- (4-aminobutyramido)-1,2,3-s-2,5,7,8-tetramethylchroman-2- triazine + carboxamido)-6-(theophylline-7-6-Hydroxy-2,5,7,8- acetamido)-1,2,3-s-triazine tetramethylchroman-2-carboxylic acid + Theophylline-7-acetic acid (121) Theophylline-7-aceticacid + 7-(6-Hydroxy-2,5,7,8-tetramethylchroman- 6-Hydroxy-2,5,7,8-tetra-2-carbonyl)-7-acetyltheophylline methylchroman-2-carboxylic acid (122)Theophylline-7-acetic acid + 6-(Methyl)-2-(4-theophylline-7-acetamido2-(4-Aminophenyl)-6- phenyl)-2-benzothiazole methylbenzothiazole (123)2-Amino-5-nitropyrimidine + 2-(6-Hydroxy-2,5,7,8-tetramethylchroman-6-Hydroxy-2,5,7,8-tetramethyl- 2-carboxamido)-5-nitropyrimidinechroman-2-carboxylic acid (124) 6-(Guanidinoacetoxy)2,5,7,8-2-(6-Guanidinoacetoxy)-2,5,7,8-tetra- tetramethylchroman-2-methylchroman-2-carboxamido-2-pyridine carboxylic acid + 2-Aminopyridine(125) 6-(Guanidinoacetoxy)2,5,7,8- 4-(6-Guanidinoacetoxy)-2,5,7,8-tetramethylchroman-2- tetramethylchroman-2-carboxamido-4- carboxylicacid + pyridine 4-Aminopyridine (126) 4-Aminopyridine +4-(Guanidinoacetamido)-pyridine Guanidinoacetic acid (127)Guanidinoacetic acid (2 mols) + 4,4′-(1,2-Diethyl-1,2-ethenediyl)bis-Diethylstilbestrol phenoldiguanidinoacetate ester (128)6-(Guanidinoacetoxy)-2,5,7,8- 2-[4,4′-(1,2-Diethyl-1,2-ethenediyl)tetramethylchroman-2-carboxylic phenol]-6-(guanidinoacetoxy)-2,5,7,8-acid + tetramethylchroman-2-carbonyl-2-phenol Dietheylstilbestrol ester(129) 6-Chloro-1,2-dihydro-17- 6-Chloro-1,2,Dihydro-17-guanidino-hydroxy-3′H-cyclopropa[1,2] acetoxy-3′H-cyclopropa[1,2]pregna-1,4,6-Pregna-1,4,6-triene-3,20- triene-3,20-dione dione + guanidino aceticacid (130) 2-Hydroxybenzoic Acid + 2-Guanidinoacetoxybenzoic acidGuanidinoacetic acid (131) 2-Hydroxybenzoic acid +2-[6(guanidinoacetoxy)-2,5,7,8- 6-(Guanidinoacetoxy)-tetramethylchroman-2-carbonyl]-2-benzoic 2,5,7,8-tetramethylchroman-acid ester 2-carboxylic acid (132) 6-Chloro-1,2-dihydro-17-2-(6-Chloro-1,2-dihydro-17-hydroxy-3′H- hydroxy-3′H-cyclopropa[1,2]cyclopropa[1,2]pregna-1,4,6-triene-3,20- pregna-1,4,6-triene-3,20-dione)-2-(6-hydroxy-2,5,7,8-tetramethyl- dione + chroman)-2-carboxylicacid ester 6-Hydroxy-2,5,7,8- tetramethylchroman-2- carboxylic acid(133) 6-Hydroxy-2,5,7,8-tetramethyl-N-(6-Hydroxy-2,5,7,8-tetramethylchroman- chroman-2-carboxylic acid +2-carboxamido)-N-amidinoacetamido-1- N-Guanidinoacetamido-1-aminophthalazine aminophthalazine (134) Cyproteronesuccinate(Na+) +17-(Cyproteronesuccinamido)-17-amino- Hydralazine phthalazine (135)4-Aminobenzamido-guanidine + 4-N-(G-Hydroxy-2,5,7,8-tetramethyl-6-Hydroxy-2,5,7,8-tetramethyl- chroman-2-carboxamido)-4-chroman-2-carboxylic acid benzamidoguanidine (136)5-(Amino)-3,5-dideoxy-D-glycero- 5-(guanidinoacetamido)-3,5-dideoxy-D-D-galacto-2-nonulosonic acid + glycero-D-galacto-2-nonulosonic acidGuanidinoacetic acid (137) Alpha-D-glucose +Alpha-D-glucosyl-1-aminoguanidine Aminoguanidine (138) Guanidineaceticacid + 6-(Theophylline-7-acetoxy)-2-5-7-8-6-Hydroxy-2,5,7,8-tetramethyl- tetramethylchroman-2-carbox-chroman-2-carboxylic acid + amidoguanidine Theophylline-7-acetoc acid(139) 6-(Guanidinoacetoxy)-2,5,7,8- 2-[6-(Guanidinoacetoxy)-2,5,7,8-tetramethylchroman-2-carboxylic tetramethylchroman-2-carbonyl]-2- acid +hydroxybenzoicacid ester Salycylic acid (140)2-(6-Chloro-1,2-dihydro-17- 17-[2-6-(N-1-Aminophthalazino-1-amido-hydroxy-3′-H-cyclopropa[1,2] propionyl)-2,5,7,8-tetramethylchroman-2-pregna-1,4,6-triene-3,20-dione)-6- carbonyl]-17-cyproterone ester(hydroxy-2,5,7,8-tetramethyl- chroman-2-carboxylic acid ester +1-(Succinamido)-1--aminophthalazine (141) 6-(Guanidinoacetoxy)-2,5,7,8-17-[6-(Guanidinoacetoxy)-2,5,7,8- tetramethylchroman-2-carboxylictetramethylchroman-2-carbonyl]-17- acid + cyproterone ester Cyproterone(142) 3,5-Dichloro-2-hydroxy- 2-[(6-Hydroxy-2,5,7,8-tetramethyl-benzylideneaminoguanidine + chroman-2-carbonyl)-2-(3,5-dichloro-6-Hydroxy-2,5,7,8-tetramethyl- 2-oxybenzylidene]-aminoguanidinechroman-2-carboxylic acid ester (143) 4,4′-(1,2-Diethyl-1,2-4-4′-(1,2-Diethyl-1,2-ethenediyl)-4- ethenediyl)-4′-guanidinoacetoxy-guanidinoacetoxyphenyl-4′-(6-hydroxy- phenyl-4′-phenol +2,5,7,8-tetramethylchroman-2- 6-Hydroxy-2,5,7,8-tetramethyl-carbonyl)-phenol ester chroman-2-carboxylic acid (144) Testosterone +17-Guanidinoacetoxytestosterone Guanidinoacetic acid (145)Aminoguanidine + 2-Acetoxy-3-5-dichlorobenzylidene-2-Acetoxy-3,5-dichloro- aminoguanidine benzaldehyde (146) Testosterone +17-(6-Guanidinoacetoxy-2,5,7,8- 6-Guanidinoacetoxy-2,5,7,8-tetramethylchroman-2-carbonyl)- tetramethylchroman-2- testosterone estercarboxylic acid (147) Estradiaol + Bis(3,17-guanidinoacetoxy)estradiaoleGanidineacetic acid (148) Estrone + 3-(Guanidinoacetoxy)-estroneGuanidineacetic acid (149) 6-Guanidinoacetoxy-2,5,7,8-3-(6-Guanidinoacetoxy-2,5,7,8- tetramethylchroman-2-tetramethylchroman-2-carbonyl)-3- carboxylic acid + estrone estroneester (150) 5-Guanidinamidopentanoic acid +1-(5-Guanidinamidopentanoyl)-2,6-di- 2,6-Di-tert-butyl-4-tert-butyl-4-methylphenol ester methylphenol (151) Prostaglandin G1(PGE1N-(PGE1carboxamido)-guanidine aminoguanidine (152) PGE1 + hydralazineN-(PGE1carboxamido)-1-aminophthalazine (153) 6-(PGE1carboxy)-2,5,7,8-N-[(6-PGE1carbonyl)-2,5,7,8-tetramethyl- tetramethylchroman-2-chroman-2-carboxamido]-1-aminophthlazine carboxylic acid + Hydralazine(154) Cyproterone + PGE1 17-(PGE1carbonyl)-17-cyproterone ester (155)Testosterone + 17-(PGE1carbonyl)-17-testosterone ester PGE1 (156)Estrone + PGE2 3-(PGE2carbonyl)-3-estrone ester (157) PGE2 +4,4′-(1,2-diethyl- 4-(PGE2carbonylphenyl)-4-4′(1,2-diethyl-1,2-ethenediyl)bis-phenol 1,2-ethenediyl)-4-phenol (158) Estradiol +PGE2 Bis(3,17-PGE2carbonyl)-estradiole ester (159)1-(Guanidinoacetoxy)-2,3- 1-(Guanidinoacetoxy)-3-(theophylline-7-propanediol + acetoxy)-2-propanol Theophylline-7-acetic acid (160)4-Aminobutyric acid + 4-N-(4-Isopropylbenzylideneamino)-4-4-isopropylbenzaldehyde butyric acid (161) Hydralazine +N-(3,4,5-Trimethoxyethyleneamino)-1- 3,4,5-Trimethoxybenzaldehydeaminophthalazine (162) 2-Methylaminobenzimidazole +2-(2,6-Dichlorobenzylideneamino)-2- 2,6-Dichlorobenzaldehydemethyl-benzimidazole (163) Aminomethylamidine +2,6-Diisopropylbenzylideneamino 2-6-Diisopropylbenzaldehydemethylamidine (164) Ethylenediamine +1,2-Bis(theophylline-7-acetamido)-ethane Theophylline-7-acetic acid (2mols) (165) 3,4,5-Trimethoxyphenyl-N-(3,4,5-Trimethoxyphenylbutyramido)-1- butyric acid + aminophthalazineHydralazine (166) Hydralazine +N-(All-cis-5,8,11,14,17-eicosapentaenoyl- All-cis-5,8,11,14,17-amino)-1-aminophthalazine eicosapentaenoic acid (167) Guanidineamido-Guanidinamidocarbonyl-1-cholinepentanoic carbonylpentanoic acid + acidester Choline (168) 1-3-Dinitro-2-propanol +1,3-Dinitro-2-guanidinoacetoxypropane Guanidineacetic acid (169)2,6-Diisopropylanillin + N-(Indole-3-methylene)-2,6-diisopropyl-Indole-3-carboxaldehyde anillin (170) Glycerol + PGE1 (2 mols)1,3-Di-PGE1-2-propanol-ester (171) 4-(3,5-Dichlorobenzylidine-4-N-(3,5-Dichlorobenzylidineamino)-1- amino)benzoic acid +guanidinobenzamide Aminoguanidine (172) 6-(Guanidinoacetoxy)-2,5,7,8-4-N-(6-Guanidinoacetoxy)-2,5,7,8-tetra- tetramethylchroman-2-methylchroman-2-carboxamido)-4-butyric carboxylic acid + acid4-Aminobutyric acid (173) Aminoguanidine + 2-(All-cis-5,8,11,14,17-2-(All-cis-5,8,11,14,17- eicosapentaenoyl)-2-oxy-1-(guanidino)-eicosapentaenoyloxy)- benzamide benzoic acid (174) Glycerol +1,3-Bis-(all-cis-5,8,11,14,17- All-cis-5,8,11,14,17-eicosapentaenoyloxy)-2-propanol eicosapentaenoic acid (2 mols) (175)Melamine + 2,4,6-Tris(-all cis-5,8,11,14,17- All-cis-5,8,11,14,17-eicosapentaeneamido)-1,3,5-s-triazine eicosapentaenoic acid (3 mols)(176) L-Arginine + N-(-2,6-Diisopropylphenyl)-L- 2,6-Disopropylanilinearginineamide (177) 2,4,6-Trimethoxybenzaldehyde +2,4,6-Trimethoxybenzylidineamino- Aminoguanidine guanidine (178)Guanidineacetic acid + N-(2,6-Dimethylphenyl)-guanidino-2,6-Dimethylaniline acetamide (179) Guanidine +Bis-N,N′-(all-cis-5,8,11,14,17- All-cis-5,8,11,14,17-eicosapentaenoylamino)-imine eicosapentaenoic acid (2 mols) (180)Hydralazine + N-(Guanidinoacetamido)-1-aminophthlazine Guanidinoaceticacid (181) 2-Amino-5-ethyl-1,3,4- 2-(2,6-Dichlorobenzylideneamino)-5-thiadiazole + ethyl-1,3,4-thiadiazole 2,6-Dichlorobenzaldehyde (182)2,6-Dichlorobenzylidene- N-(2,6-Dichlorobenzylideneamino)-N′-aminoguanidine + (theophylline-7-acetyl)-guanidine Theophylline-7-aceticacid (183) 2-(3,4-Dihydroxyphenyl)-N-(6-Hydroxy-2,5,7,8-tetramethylchroman- 2-hydroxyacetaldehyde +2-carbonyl)N′-(3,4-dihydroxyphenyl)-2- Trolox-guanidineamide(R)-or-2-(S)-hydroxyethylguanidine (184) Megosterol +17-(Guanidinoacetoxy)-megostrol Guanidinoacetate (185)Medroxyprogesterone + 17-(Guanidinoacetoxy)-medroxy- Guanidinoaceticacid progesterone (186) Hydroxyprogesterone +17-(Guanidinoacetoxy)-progesterone Guanidinoacetic acid (187)[Z]-2-[4-(1,2-Diphenyl- [Z]-2-[4-(1,2-Diphenyl-1-butenyl)-1-butenyl)-phenol + phenoxy]-guanidineacetate ester Guanidinoacetic acid(188) 2-Guanidinobenzimidazol + 2-(Indole-3-methyleneamino)-2-Indole-3-carboxaldehyde amidinobenzimidazol (189) Phenylacetic Acid +Phenylacetamidoamididine Guanidine (190) 1,4-Diguanidinobutane(Commercially available product as arcaine) (191)2,6-Dichlorobenzaldehyde + 3,7-Dihydro-8-(2,6-dichlorobenzylidene3,7-Dihydro-8-amino- amino)-1,3,7-trimethyl-1H-purine-2,6-1,3,7-trimethyl-1H- dione purine-2, 6-dione (192)4,4′-[Pentanediylbis(oxy)] bis-benzenecarboximidamide (Commerciallyavailable as pentamidine) (193) Cytosine + 2,6-Dichlorobenzaldehyde4-N-(2,6-Dichlorobenzylideneamino)-2- oxypyrimidine (194)3,4,5-Trimethoxybenzaldehyde + 3,5-Bis(3,4,5-trimethoxybenzylidene3,5-Diamino-1,2,4-triazole amino)-1,2,4-triazole (195) Trolox +3,5-Bis-(6-hydroxy-2,5,7,8-tetramethyl- 3,5-Diamino-1,2,4-triazolechroman-2-carboxamido)-1,2,4 triazole (196)5-Hydroxyindole-3-acetaldhyde + 3-(5-Hydroxyindole-3-ethylamino)-5-3,4,5-Trimethoxybenaldehyde + (3,4,5-trimethoxybenzylideneamino)-3,5-Diamino-1,2,4-triazole 1,2,4-triazole (197) 8-Aminocaffeine +3,7-Dihydro-8-N-(2-acetoxybenzamido)- Acetylsalicylic acid1,3,7-trimethyl-1H-purine-2,6-dione (198) Cytosine +4-N-(1-Glucosylamino)-cytosine D-glucose (199) Theophylline-7-aceticacid + 3-(2,6-Dichlorobenzylideneamino)-5- 2,6-Dichlorbenzaldehyde +(theophylline-7-acetamido)-1,2,4- 3,5-Diamino-1,2,4-triazole triazole(200) Trolox + 3-(6-Hydroxy-2,5,7,8-tetramethylchroman- Betaine +2-carboxamido)-5-(N,N,N-trimethylmethan- 3,5-Diamino-1,2,4-aminiumcarboxamido)-1,2,4-triazole triazole (201) Theophylline-7-aceticacid + 3-(-2-Acetoxybenzamido)-5-(theophylline-3,5-Diamino-1,2,4-triazole + 7-acetamido)-1,2,4-triazole Acetylsalicylic(202) Theophylline-7-acetic acid + 3-(-2-Guanidinoacetoxybenzamido)-5-2-Guanidinoacetoxybenzoic (theophylline-7-acetamido)-1,2,4- acid +triazole 3,5-Diamino-1,2,4-triazole (203) 8-Aminocaffeine +3,7-Dihydro-8-(2-guanidinoacetoxyphenyl- 2-Guanidinoacetoxy-carboxamido)-1,3,7-trimethyl-1H-purine- benzoic acid 2,6-dione (204)P-Hydroxyanilin + N-(4-Guanidinoacetoxy)-guanidino- Guanidinoacetic Acidacetanilid (205) 8-Aminocaffeine + 3,7-Dihydro-8-(6-hydroxy-2,5,7,8-Trolox tetramethylchroman-2-carboxamido)-1,3,7-trimethyl-1H-purine-2,6-dione (206) Trolox + Cytosine +4-N-(-6-Guanidinoacetoxy-2,5,7,8-tetra- Guanidineacetic Acidmethylchroman-2-carboxamido)-4-2- (hydroxy)-pyrimidine (207) Trolox +8-Aminocaffeine + 3,7-Dihydro-8-N-(-2-guanidinoacetoxy- Guanidineaceticacid 2,5,7,8-tetramethylchroman-2- carboxamido)-1,3,7-trimethylxanthine(208) Thioctic acid N-(1,2-Dithiolane-3-pentanamido)- (Alpha-lipoicacid) + guanidine Aminoguanidine (209) Thioctic acid + 3,5-3,5-Bis-(1,2-dithiolane-3-pentanamido)- Diamino-1,2,4-triazole1,2,4-triazole (210) Aminoguanidine + 3,3′-Thiodipropanamidoguanidine3,3′Thiodipropionic acid (211) Maleic Acid +Cis-1,2-ethylene-bis-(carboxamido)- Aminoguanidine guanidine (212)Theophylline-7-acetic acid + 3-(Glycylamido)-5-(theophylline-7-3,5-Diamino-1,2,4-triazole + acetamido)-1,2,3-triazine Glycine (213)8-Aminocaffeine + 8-[2-(4-Amino-3,5-dichlorophenyl)-2- 2-(4-Amino-3,5-hydroxyethylene]-8-imino-1,3,7- dichlorophenyl)-2- trimethylxanthinehydroxyethylaldehyde (214) Cafaminol + 8-[(2-GuanidinoacetoxyethylGuanidineacetic acid methylamino)-caffeine (215) 8-Aminocaffeine +8-(4-Aminobutyramido)-1,3,7-trimethyl- GABA xanthine (216)2′-Deoxyadenosine + 9-(2′-Deoxy-5′-guanidinoacetoxy)-9-beta-Guanidineacetic acid D-ribofuranosidoadenine or2′-deoxyadenosine-5-′guanidinoacetic acid ester (217)N-(-4-)Chlorophenyl)-N′- (1-methyl-ethyl)imido- dicarbonimidic diamide(Available commercially as chlorguanide) (218) 4-Chlorobutyric Acid +4-N-(2,6-Dimethoxybenzylideneamino)-4- Dimethoxybenzylidene-amidinobutyric acid guanidine (219) 4-Chloro-3,5-xylenol +2-(2,6-Dimethyl-4-hydroxyphenylamino)- 2-Hydrazinoimidazole2-aminoimidazole (220) 8-Chlorocaffeine +8-N-(5-Hydroxyindole-3-ethylamino)-8- 5-Hydroxytryptamine(1,3,7-trimethyl)-xanthine (221) 7-(2-Chloroethyl)-theophylline +7-(Guanidinoaminoethyl)-7-(1,3- Aminoguanidine dimethyl)-xanthine (222)8-Chlorocaffeine + 4-N-(8-Amino-1,3,7-trimethylxanthine)-4-4-Aminobutyric Acid butyric acid (223) 4-Amidinobenzamide +N-(Diphenylmethyl)-4-(amidino)- Chlorodiphenylmethane Benzamide (224)8-Chlorotheophylline + 1-N-(Theophylline-8-amino)-1- Hydralazineaminopthalazine (225) 2-Chloroadenosine +6-Amino-2-guanidinopurineriboside Guanidine (226) 4-Chlorophenoxyacetic4-Chlorophenoxyacetamidoguanidine acid + Aminoguanidine (227)4-Chlorophenoxyacetamidoguanidine + 4-Aminoguanidinophenoxyacetamido-Aminoguanidine guanidine (228) 2-Amino-1,3,4-thiadiazole +2-(8-caffeineamino)-1,3,4-thiadiazole 8-Chlorocaffeine2-N-(1,3,7-Trimethylxanthine-8-amino)- 1,3,4-thiadiazole (229)Cyheptamide + 8-N-(10,11-Dihydro-5H-dibenzo[a,d] 8-Chlorocaffeinecycloheptene-5-carboxamido)-8-(1,3,7- trimethyl)-xanthine (230)4,6-Dichloro-2-(methylthio)- 4,6-Diaminoguanidino-2-(methylthio)-pyrimidine + pyrimidine aminoguanidine (231) 4-Chlorophenoxyacetamido-5-N-(10,11-Dihydro-5H-dibenzo[a,d] guanidine +cycloheptene-5-carboxamido)-5- cyheptamide (phenoxyacetamido)-guanidine(232) 3,5-Diamino-1,2,4-triazole +3,5-Bis-(7-methyl-8-theophyllineamino)- 8-chlorocaffeine 1,2,4-triazole(233) Biotin + 4- N-(Hexahydro-2-oxo-1H-thieno[3,4-d]- Amidinobenzamideimidazole-4-pentanoyl)-4- amidinobenzamide (234) Biotin +N-(Hexahydro-2-oxo-1H-thieno[3,4-d]- Aminoguanidineimidazole-4-pentanamido-4-guanidine

The major sub-genuses of compounds listed herein, include compoundshaving an acyclic guanidino moiety, such as the first compound in TableI, and compounds wherein the guanidino moiety is part of an aromatic,cyclic group, such as the s-triazine group, as shown, for example, bythe fourth compound in Table I, as well as compounds wherein theguanidino group is part of a non-aromatic, either saturated orunsaturated cyclic group, such as in Compounds 2 and 92–95.

The conditions which have been found to be effective in carrying out thepreparation reactions exemplified by Table II, are substantially thesame as those set forth in the co-pending application Ser. No. 689,712.

Preferably, these guanidino compounds of the present invention can betransformed from the free base into the form of their physiologicallyacceptable salts by customary methods, as described, for example, inU.S. Pat. No. 3,975,533. Useful such salts, include, for example, thesalts of inorganic acids, such as hydrochloric, hydrobromic, hydriodic,sulfuric or phosphoric acids, as well as of organic acids includingacetic, malic, ethionic, malonic, citric, benzoic, succinic, sulfamic,lactic, tartaric, cinnamic, gluconic, ascorbic, and pamoic acids. Thecompounds can also usefully form quaternary ammonium salts with avariety of organic esters of sulfuric, hydrohalic and aromatic sulfonicacids. Among such esters are methyl chloride and bromide, ethylchloride, propyl chloride, butyl chloride, isobutyl chloride, benzylchloride, and bromide, phenethyl bromide, naphthylinethyl chloride,dimethylsuif ate, diethylsulfate, methylbenzene sulfonate, ethyltoluenesulfonate, ethylene chlorohydrin, propylene chlorohydrin, allyl bromide,methallyl bromide, and crotyl bromide.

Although it is preferred that compounds having anesthetic properties beadministered parenterally, all of these compounds can be usefullyadministered orally, or by other means well known to the art.

Thus, the compounds of the present invention can be used as medicamentsfor mammals in the form of pharmaceutical preparations suitable foradministration orally, parenterally, intraperitoneally, intravenously,by dermal patch, or as nasal spray, depending on their intended use andactivity. These compounds can be administered in a substantially pureform, with other active ingredients which may be desirable, or dissolvedor diluted in a suitable pharmaceutical vehicle. The compounds aregenerally crystalline solids or oils which can be at least partiallysoluble in commonly used organic solvents. They are also generallysoluble in liquid pharmaceutical vehicles, including water, especiallywhen they are formed as their physiologically acceptable salts.Generally, the acid addition salts are more soluble in water than arethe free base compounds, per Se. Formulation in a pharmaceutical vehiclecan be carried out in accordance with techniques and in vehicles whichare wholly conventional to those skilled in the art for the intendedmode of administration.

Non-parenteral modes of administration can be preferable, especiallywhere anaesthesia is not sought, for the compounds of this invention.For example, preparations for oral administration can be in eitherliquid or solid form, including for example syrups, elixirs, powders,capsules or tablets. The materials are preferably prepared for unitdosage form as powders which are preferably pressed into tablets orsuitably encapsulated in, for example, conventional gelatine capsules.Any powders or compressed tablets can generally also comprise theusually suitable excipients and/or diluents, such as starch, lactose,stearic acid, magnesium stearate, dextrin or polyvinylpyrrolidone.

Other suitable solid carriers include magnesium stearate, sicarylalcohol, talc, vegetable oils or fats, alcohols such as benzyl alcohols,gums, waxes, alkylene or polyalkylene glycols, such as propylene glycolor polypropylene glycol and any other well known carriers.

Suitable sterile solutions or suspensions can be prepared for parenteralor intraperitoneal administration, e.g., intravenous, containing forexample water, dextrose, physiological saline, benzyl alcohol, ethyloleate, methylcellulose, dimethyl sulfoxide, polyethylene glycol liquid,as well as other liquid excipients well known in the pharmaceutical orveterinary art. Other auxiliary pharmaceutical materials which can bepresent include preservatives, stabilizers, wetting or emulsifyingagents, or osmotic salts or buffering agents, as is well known to thepharmaceutical or veterinary art. As these formulations are generallywell known and conventional, more specific instructions need not bepresented for purposes of defining this invention.

Typical, illustrative species of this class of pharmaceuticals are thefollowing:

-   -   1-(2–Chloro-6-(trifluoromethyl)-benzylideneamino)-guanidine;    -   1-(2–Chloro-3,6-bis        (trifluoromethyl)-benzylideneamino)-guanidine;    -   1-(2–Chloro-6-bromobenzylideneamino)-guanidine;    -   1-(2,6-Dibromobenzylideneamino)-guanidine;    -   1-(2-Bromo-6-methylbenzylideneamino)-guanidine;    -   1-(2, 3, 6-Tribromobenzylideneamino)-guanidine;    -   1-(2-Chloro-6-propylbenzylideneamino)-guanidine;    -   1-(2,4,6-Trichlorobenzylideneamino)-guanidine;    -   1-(2,6-Dichloro-4-methylbenzylideneamino)-guanidine;    -   1-(2-Bromo-6-fluorobenzylideneamino)-guanidine;    -   1-(2,6-Dichlorobenzylideneamino)-2-propynyl-guanidine;    -   1-(2,6-Dichlorobenzylideneamino)-1,2,3-trimethyl-guanidine;    -   1-(2,6-Dichlorobenzylideneamino)-, 2,3-vinylene-guanidine;    -   1-(2,6-Dibromo-4-inethylbenzylideneamino)-guanidine;    -   1-(2-Chloro-alpha-methylbenzylideneamino)-guanidine        hydrochloride;    -   1-(2-(Trifluoromethyl)-alpha-methylbenzylideneamino)-guanidine        hydrochloride;    -   1-(2-Chlorobenzylideneamino)-guanidine;    -   1-(2,4-Dichloro-alpha-methylbenzylideneamino)-guanidine,

Arcaine & Pentamidine, and the corresponding acid addition salts of thelower carboxylic acids, i.e., of fewer than six carbon atoms.

The pronounced hypothermia effect from the administration of theseguanidino compounds can be a useful adjunct to the anesthetic effect,especially during lengthy or critical surgical procedures, such asduring neurosurgery, cardiovascular surgery or organ transplantprocedures. Specifically, the core temperature of a mammal can beallowed to drop by as much as about 15 degrees C., or even more, and bemaintained at that low temperature without any danger to the organism.The lower temperatures decrease the possibility of and/or prevent fromsignificant damage to major organs, e.g., the brain, during surgery, inthe event of any serious malfunction or error. Further, it provides fora relatively bloodless surgical field of operation, and thus may obviateintentional stoppage of blood flow.

Although the core temperature drops significantly, the mammal is evenless susceptible to injury from extreme variations of temperatures thanan untreated mammal. For example, after administration of a guanidinocompound, such as guanabenz, a mammal can be subjected to extremely lowor elevated temperatures, e.g. as low as minus 20′ C., or as high as 42′C., without injury. This resetting of the thermoregulator can provideprotection for mammals during thermogenic or cryogenic surgicalprocedures.

Most useful from a clinical perspective, the guanidino compounds, aswell as their antagonists, are easily titratable; and thus it ispossible independently, and at almost any desired rate, to counteractthe anesthetic or hypothermic effect of guanidino compounds by the useof a suitable antagonist. Specifically, for example, if it is desired toblock or terminate the hypothermic effect, an alpha 2-adrenoceptorantagonist can be used, either prior to, together with, or after theadministration of guanabenz, which will cause the core temperature toreturn towards and be maintained at, about normal levels, substantiallywithout reducing the anesthetized condition of the mammal. Indeed, by,preferably, first administering a hypothermia antagonist, prior toadministration of the guanidino compound, the anesthetic effect may beenhanced, and occurs more quickly. An example of such effect-specificalpha₂-antagonists, is tolazoline, and e.g., the compounds 98–101, 162,163 in Tables I and II.

Contrariwise, if an anesthetic effect is not desired, but a hypothermiceffect is desired, it is possible either to reduce or eliminate theanaesthetic effect of a guanidino compound having both activities, or toselect a compound which does not have anesthetic properties, but doeshave hypothermic properties. If it is desirable to administer one of theguanidino compounds, without anesthetic effect, while maintaining thehypothermic effect, the guanidino compound can be combined with, e.g., axanthine, such as aminophylline or isopropylmethyl xanthine, or abeta-agonist, such as isoproterenol or clenbuterol. Some antagonistswill reverse both the hypothermic and anesthetic effects of guanidinocompounds. Examples of such a selective alpha2-antagonist are Yohimbine,and compounds 96, 97 and 122 in Tables I and II. The effect can also bepartially reversed, or reversed in stages, if desired, by administeringseveral smaller aliquots of the antagonist. Interestingly, Naloxone, wasnot found to be a useful antagonist, indicating that the anesthesia isnot induced through the opiate receptors.

Certain of the compounds produce a profound hypothermia, but withoutanesthetizing. In addition, it has been found that these guanidinocompounds have other useful properties which complement or are inaddition to the above two effects. Table III, following, sets forth alist of the other properties of these guanidino compounds, which arisefrom their alpha-adrenergic agonist activity, combined with any inherentactivity of the reactants chosen to achieve the final compound.

TABLE III The Activities and Properties of the Guanidino and OtherAgonist or Antagonist Compounds of This Invention 1) Treatment andprevention of Neurological Damage, by disease or trauma, e.g., Retardprogression of and/or ameliorate neurological degenerative disease suchas: a) Amyotrophic lateral sclerosis b) Parkinson's Syndrome or Diseasec) Alzheimer's Disease d) Cerebral Palsy e) Muscular Dystrophy f)Multiple Sclerosis g) Traumatic CNS injury (head trauma and  spinal cordtrauma Paraplegia and  Hemiplegia); h) Cerebrovascular Accidents (CVS) Minimizes Reperfusion Injury and  Thromboemblic Stroke; i) minimizes orinhibits the side-effects  of opiate withdrawal 2) Antispasticity andmuscle relaxant 3) Bronchodilator (treats Emphysema and asthma, controlsexaggerated mucous secretions) 4) Tonic stimulation of motor neurons;Retards and/or stops the loss of muscle mass 5) Serotonergic agonistexcites coordinated motor activity and immediate weight bearing rapidlyin spinal cord injured mammals treated with adrenoceptor active drugs 6)Inhibits formation of tight three dimensional dense collagen (scartissue) formation that occurs during injury induced hypoxia 7) Stimulaterelease of the growth hormone and other growth factors which contributeto regeneration and repair of nerve tissue. 8) Increases blood perfusionpressure; treatment of Traumatic Spinal, Septic and Cardiovascular Shock9) Antiinflanimatory (used in acute inflammation/Edema from Arthritis,Rheumatoid or osteo-arthritis) 10) Analgesic (Cluster headaches,migraine) 11) Antioxidants; also can be used alone or in conjunctionwith other drugs for treatment of carcinoma during radiation therapy oraccidental exposure to radiation 12) Antifungal (may be used alone or inconjunction with other drugs for treatment of HIV infections and AIDS);Topically for dermatologically inflammatory conditions; as from eczemaand psoriasis 13) Cause Retardation or atrophy of tumors 14) Treatmentof Nephrosclerosis, systemic Lupus erythematosis; Scleroderma andallergic reactions 15) Treatment of Gastrointestinal stress-inducedulcers; anti-emetic; pro-kinetic (increase or retard G.I motility) 16)Nasal decongestant (vasoconstriction of the mucosal membrane) 17)Anti-hypertensive 18) Inhibition of excess adipose deposition(Enhancement of lean body mass) 19) Anti-hyperlipoproteinemic (treatmentof Atherosclerosis, retards plaque formation on the arterial walls) 20)Anti-epileptic 21) Anti-coagulant (blood) 22) Anesthetic, 23)Antipyretic, Hypothermic 24) Calcium channel blocker 25) Anti-coloncarcinoma 26) Androgenic antagonist 27) Estrogenic antagonist (breastcancer treatment) 28) Anabolic (with little or no virilization) 29) NMDA(glutamate) receptor antagonist

Except for items numbered 22 and 24–28 in Table III, substantially allof the guanidino compounds of this invention, as a result of theirstructure-activity relationship, are potent with respect to all of theabove activities. However, as would be expected, various compounds havedifferent, higher levels of, activities and properties which are listedas “Specific Properties”, with the Compounds numbered, in Table IV,below, according to the numbers in Tables I and II.

TABLE IV Example No. Specific Properties 1 10, 15 2 10, 15 3 10, 23 4 5,22 5 5, 23 6 9, 15, 21, 23, 25 7 3, 15, 22, 23 8 15, 22, 23 9 3, 10, 12,15, 23, 25 10 10, 12, 23, 25 11 23, 24 12 22, 23 13 22, 23 14 2, 21, 22,23 15 2, 23 16 2, 22, 23 17 22, 23 18 2, 15, 22, 23 19 2, 15, 23, 24 202, 15, 22, 23 21 2, 15, 23 22 2, 15, 23, 24 23 3, 8, 12, 25 24 15, 22,23 25 2, 15, 23 26 2, 10, 23 27 8, 17 28 5, 23 29 5, 22, 23 30 15, 23 312, 3, 15, cholinergic 32 1, 15, cholinergic 33 2, 12, 13 34 2, 12, 13 353, 12, 15 36 3, 15 37 5, 12 38 5 39 2, 3, 12, 15 40 10, 12, 15, 25 41 2,4 42 10, 12, 15, 24 43 1, 9, 10, 11, 19, 23 44 1, 3, 23 45 1, 2, 8, 1546 1, 2, 12, 22, 23 47 8, 23, 24 48 1, 2, 5, 23 49 1, 2, 8 50 2, 15, 22,23 51 2, 15, 17 52 5, 23 53 3, 8, 14, 23 54 3, 8, 14, 23 55 1, 2, 23 561, 2, 14, 24 57 3, 8, 14 58 2, 12, 13, 14 59 2, 12, 13, 14 60 2, 12, 13,14 61 2, 12, 13, 14 62 2, 12, 13, 14 63 2, 10–15, 19 64 2, 10–15, 19 655, 23 66 2, 22–24 67 2, 10, 14, 15 68 2, 3, 22, 23, 24 69 2, 3, 22, 2370 2, 3, 8, 12, 23 71 2, 9, 10, 12, 25 72 3, 5, 23 73 2, 10 74 5 75 2,3, 8, 16 76 2, 3, 22, 23 77 10, 12, 25 78 5 79 10, 12, 25 80 10, 12, 2581 10, 12, 25 82 3, 10, 12, 25 83 3, 10, 12, 25 84 3, 10, 12, 25 85 2,15, 22, 23 86 2, 19, 23 87 2, 10, 24 88 10, 12, 25 89 10, 12, 23, 25 908, 9, 10, 11, 13, 14, 19 91 9, 10, 12, 25 92 2, 13, 14, 22, 23 93 2, 3,14, 23 94 2, 8 95 2, 10, 20 96 3, adrenergic antagonist, 12 97 3, 2, 2,antagonist, 12 98 adrenergic antagonist 99 adrenergic antagonist 100adrenergic antagonist 101 adrenergic antagonist 102 3, 14, 16, 17antagonist 103 5 104 2 105 9, 11, 13, 14, 15, 19 106 2, 3 107 2, 17 1082, 13, 22, 23 109 22, 23 110 8, 9, 10, 11, 13, 14, 19 111 10, 22, 23 1125, 8 113 8, 9, 10, 16 114 8, 9, 10, 11, 13, 14, 19 115 2, 8, 23 116 8,9, 10, 11, 13, 14, 19 117 8, 9, 10, 11, 13, 14, 19 118 5, 10, 11 119 9,10, 11, 12, 13, 14, 19 120 2, 11, 12, 13, 14, 19 121 3, 11, 12, 15 1223, adrenergic antagonist, 15, 7 123 2, 8, 9, 10, 11–15 124 2, 8, 9, 10,11, 14 125 5, 8, 9, 10, 11, 14 126 5, 9, 10 127 27 128 27 129 26 130 9,10, 12, 25 131 9, 10–15, 25 132 11, 26 133 8–15, 17 134 8, 11, 26 1359–15 136 9–11, 14 137 2, 9, 10 138 2, 3, 8–14 139 2, 9–14, 23, 25 140 26(ESP Topical to treat male pattern baldness) 141 3, 8–16, 26 142 11, 25,27 143 27 144 26, 28 145 3, 8–16, 25 146 19, 26, 28 147 27 148 27 14919, 27 (possible injection into corpus cavernosum or insertion intouretha to bring about erection in impotent male) 150 2, 9, 11 151 6–11(anti-impotence) 152 6–11 (anti-impotence) 153 6–11 (anti-impotence) 15426 155 26, 28 156 27 (some agonist activity) 157 27 (some agonistactivity) 158 27 159 3, 8, 10 160 2, 4, 6 161 10, 17 162 14, 17adrenergic antagonist, 22, 23 163 14, 17, adrenergic antagonist, 22, 23164 3, 15, anesthesia antagonist 165 8, 17 166 8, 17, 19 167 Adrenergic,cholinergic, 22, 23 168 8, 9, 12, 22, 23 169 5, 22, 23 170 8, 9, 12,Vasodilator 171 10, 12, 22, 23 172 2, 8, 9, 10, 11, 19 173 8–11, 19, 21,25 174 8–11–19 175 9, 10, 19, 22, 23 176 2, 9, 17, 22, 23 177 2, 13–15,22, 23 178 2, 13, 22, 23 179 17, 19, 22, 23 180 8–10, 13, 14, 22, 23 1823, 7–15 183 8–16, 19 184 27, Progestin, androgenic 185 27, Progestin,androgenic 186 1927, Progestin, androgenic 187 27, Progestin 188 5, 9,10, 13 189 2, 4, 6, 10 190 1, 2, 4, 6–11, 15–19, 29 191 1–4, 6–13, 16–19192 1, 2, 8–10, 15, 29 Adrenergic antagonist 193 1, 2, 8–10, 13, 17, 22,29 194 1, 2, 4, 5, 8–10, 17 195 1, 2–5, 7–11, 17, 21 196 1, 4–5, 8 1971–4, 6–13, 19, 21, 23, 25 198 1–4, 6–12, 14, 15, 22, 29 199 1, 4, 6–13,19, 21, 25 200 1, 2–4, 8–11, 14, 17, 21 201 1–5, 8–14, 19, 20, 23, 25202 1–14, 18–20, 23, 25 203 1–14, 16, 18–20, 23, 25, 29 204 1, 2, 6–10,13–15, 17, 23 205 1, 2–5, 7–11, 14–17, 21, 22 206 1, 2, 8–10, 13, 17,22, 23, 29 207 1, 2–10, 13, 17, 22, 23, 29 208 1, 4, 6–11, 14, 21, 22209 1, 4, 8–14, 17, 22 210 1, 2, 6–10, 15, 17, 29 211 1, 2, 6, 11, 15,17, 29 212 1, 2, 8–11, 13, 17–19, 23 213 1–6, 8–12, 16–20 214 1–12, 15,16, 19, 29 215 1–6, 8–12, 15–20 216 1–4, 6–12, 14, 15, 22, 29 217 1, 4,6–9, 16, 17, 19 antimalarial 218 1, 4, 6–10, 16, 17, 23, 29 219 1, 4,6–10, 15, 16, 17, 22, 23, 29 220 1–10, 17, 23, 26 221 1–4, 6–10, 14,16–19, 23, 29 222 1–4, 6–10, 4, 16–19, 23, 29 223 1, 2, 4, 6, 9, 10, 14,15, 17, 23, 29 Adrenergic antagonist 224 1–4, 6–15, 17, 19, 23 225 1, 2,4, 6–9, 13–15, 17, 29 226 1, 2, 4, 6–10, 17, 22, 23, 29 227 1, 2, 4,6–10, 17, 23, 29 228 1, 2, 4, 6–19, 23, 29 229 1–10, 16–17, 23 230 1, 2,4, 6–12, 15, 17, 22, 23, 29 231 1, 2, 4–10, 16–17, 22, 23, 29 232 1, 2,4, 6–19, 22, 23, 29 233 1, 2, 4, 6, 9, 10, 14, 15, 17, 23, 29Antialopecia, adrenergic antagonist 234 1, 2, 4, 6–10, 14, 15, 17, 23,29Behavioral Responses:

Following administration of the anesthesia-antagonist, or after theguanidino compound has been metabolized, i.e., about three-to-eighthours after administration (depending upon the dose), the treated mammalawakens, giving the appearance of being well rested and alert, withoutthe “hang over” and other debilitating effects associated with theadministration of commonly used general anaesthetics. Although,guanabenz is well known for its hypotensive effect, it has relativelymoderate hypotensive effect in the supine position, and therefore,during surgery. This property is shared by other guanidino compounds.

To induce anesthesia, the active anesthetic agent, e.g., guanabenz, ispreferably administered intravenously with an initial unit dosage of atleast about 4 mg and preferably, to a large mammal, from about 8 mg toabout 25 mg, but optimally not more than about 15 mg. It is preferableto titrate drugs slowly to achieve the desired level of anesthesia andto avoid overdosage, and possible hypertensive spike, which results fromadministration as a bolus; the guanidino compound is preferablyinitially administered over a period of about two to about five minutes.

Oral administration, specifically to achieve hypothermia or the othereffects listed in Table III, above, requires from about 20 mg. to about50 mg. of a guanidino compound. For example, in laboratory rats it hasbeen found that the I.P. administration of 12 mg guanabenz per kilogramof body weight is a sufficient amount to initially place the rats in ananesthetized condition; when dealing with a 60 to 75 kg mammal it hasbeen found that the total amount administered in the initial singledose, e.g., by intravenous injection, need not be greater than about 0.5mg/kg, and preferably in the range of from about 0.05 to about 0.3mg/kg, to provide the desired anesthetic and hypothermic effect.

The anesthetic-effective guanidino compounds, e.g., the acetate additionsalt of guanabenz, are most preferably administered intravenously, in 5to 10 ml of a 5% dextrose solution, containing between approximately 1and about 2 mg/ml of guanabenz, or an appropriate amount of anotherguanidino compound, to induce anesthesia. The guanidino compounds canalso be administered in other suitable liquid carriers well known tothose skilled in the art, such as physiologic saline solution, benzylalcohol, ethyloleate, methylcellulose, or polyethylene glycol. After thesubject mammal is initially placed under anesthesia, the anestheticstate can be maintained by, e.g., a continuing intravenous drip usingthe 5% aqueous dextrose solution. To induce anesthesia the guanidinocompound in solution is preferably administered discontinuously in anamount of from about 1.0 to about 2.0 mg per minute, over a period offrom about 2 to about 5 minutes. It can then be titrateddiscontinuously, via an intravenous drip, in 50 to 100 ml 5% dextrosesolution, containing 0.1 to 0.2 mg/ml of the guanidino compound for aperiod of up to 24 hours, or even longer if necessary, to maintain thestate of anesthesia/hibernation. Rats have been maintained for up to 12days in a pseudo-hibernating condition. This condition can increase thesuccess rate for surgery, and provide an extremely effectiverecuperative condition after a surgical procedure for traumatic injury.

To provide purely hypothermic activity, it is usually advisable toadminister drugs orally, unless it is not feasible to do so, for examplewhen the mammal is unconscious.

As is shown in Table II, above, most of the novel compounds of thepresent invention in accordance with Formulae I, II, or III, above, canbe prepared by reacting at least two compounds; the first compound (“A”)includes a guanidino group, which can be present, for example, as partof a heterocyclic group, e.g., an amino-triazine group, anamino-arylimidazole, e.g., 2-aminobenzimidazole, or 2-aminoimidazolinegroup, (or an equivalent thio- or oxo-2 compound where one of thenitrogen atoms forming any of the above groups is replaced by a sulphuratom or oxygen atom, respectively); the second compound (“B”) comprisesa lipophilic moiety, and a co-reactive substituent selected, forexample, from the group of beta-hydroxyphenylacetic acid, aldehyde oramine, coreactive with a moiety on Compound “A”. More generally, one ofthe above A and B compounds preferably include a free and reactivecarbonyl group, (such as a carboxyl group, and aldehyde group), or ahydroxyl group or amino (—NH2) group, or other groups. The other of theabove A and B compounds includes another group or groups, which aremutually reactive with the substituent on the first compound. Mostpreferably, the “A” compound reacts with the B compound through one ofthe primary or secondary amino nitrogen atoms forming part of theguanidino or aminoguanidino moiety.

Suitable group “A” reactant compounds include guanidine, aminoguanidine,guanidineacetic acid, 2-guanidinobenzimidazole, 2-aminoimidazole,2-aminodihydrothiazine, 2-hydrazinoimidazoline,3,5-Diamino-1,2,4-triazine, 2,4,6-triamino-1,3,5-s-triazine,2,4-diamino-6-phenyl-1,3,5-s-triazine,2,4-bis(diethylamino-6-hydrazino-1,3,5-s-triazine,4-methyl-4H-1,2,4-triazole-3-thiole, 4,5,diphenyl-2-imidazole-thiole,2-(4-aminophenyl-6-methyl)-2-benzothiazole, 2-aminopurines,2-aminopyrimidines, 2-aminocytidine, other acyclic or cyclic groupscontaining the guanidino moiety as defined by formula I, above, andtheir acid addition salts.

The following examples provide common procedures for preparing specieswhich are preferred for their activity within the group of novelcompounds constituting the invention. These procedures are similar tomethods commonly used in the preparation of organic chemicals, and aspreviously described in my copending application Ser. No. 189,464, andits continuation, serial No. 689,712. These illustrative compoundswithin the present invention may, of course, also be prepared by otherpaths.

EXAMPLE 1 Preparation of Bis-(4-methylbenzylidene)-Guanidine

4-Methylbenzaldehyde (MBA) (0.50 mols–60 grams) is admixed withguanidine hydrochloride (0.25 mols, 25 grams) in molar ratio of 2:1.They are then heated under reflux in 150 ml of toluene under a DeanStark water collector trap for approximately 17 hours to collect thetheoretical amount of H₂O evolved. The hot solution is rapidly decantedto ensure the removal of insoluble residues. The solution is thenevaporated to dryness on a rotary evaporator. The crude immine is thenrecrystalized twice from absolute ethanol.

The resultant product is shown as Number 3 in Tables I and II.

EXAMPLE 2 Preparation2,4-Bis-(2,6-dichlorobenzylideneamino)-6-(5-hydroxyindole-3-ethylamino)-1,3,5-s-triazine(Compound. 4)

This asymmetrical compound, i.e., which has more than one substituent onthe amino groups of melamine, is prepared by the following procedure:

In a 5L. 3-neck flask, are combined 63 g. (0.50M) of melamine and 200 mlof Bis-(2-methoxyethyl)-ether. This is heated to 85° C. under nitrogen,with a Herschberg stirrer. Through a pressure-equalizing separatoryfunnel, there is added dropwise, over a 4-hr. period, a mixture of 132.5g of 5-benzyloxy-indole-3-acetaldehyde and 174 g of2,6-dichlorobenzaldehyde, in 750 ml of warm Bis-(2-methoxyethyl) ether.During this period the temperature is slowly elevated to 120′ C., andthe elevated temperature is maintained for an additional 8-hr. period.At the end of this period, the solvent is removed under high vacuum on arotary evaporator.

The resultant oil is chromatographed on Florisil, using a mixture ofethylacetate/benzene/pyridine (8:2:0.01), to obtain the product(Compound 4) in a yield of 34%. Electrospray-mass spectrometry indicateda single peak of m/e (613). The product is homogeneous on the followingthree thin-layer chromatographic systems

-   ethylacetate:benzene:pyridine (8:2:0.01);-   butylacetate:butanol:ether:pyridine (8:3:1:0.01);-   methylacetate:hexane:pyridine (10:2:0.01)

EXAMPLE 3 The Preparation of 2-(Phenylacetyl)-2-hydrazinoimidazole(Compound 15)

Phenylacetic acid (PAA), 0.037 moles (5 g) was heated under reflux withan excess of SOCl₂ for 60 minutes at a temperature of 75–80° C. Afterthe reaction was completed, the excess SOCl₂ was eliminated by vacuumevaporation, using a water pump (40–50° C.). This process was repeatedtwo to three times, each time adding benzene to aid in elimination ofSOCl₂ and yielding phenylacetyl chloride (PAC). Then, 0.018 mole of2-hydrazino-2-imidazoline. HBr (3.5 g) was suspended in ether and shakenwith 2N NaOH (2–5 equivalents) on an ice bath, until it was completelydissolved. The PAC was then added dropwise very slowly from a funnelwith vigorous shaking. Excess NaOH was present to drive the reaction tocompletion. After the addition of PAC, the mixture was stirred at 0° C.for an additional 15–30 minutes. The ether layer was washed with water,then with saturated NaHCO₃. It was then dried over Na₂SO₄, filtered andwas brought to complete dryness. The solid residue from the ether layerwas then crystallized from an ethanol-water mixture (70–80% ethanol).The yield, was approximately 55% without subjecting the residual amideto further separation from the aqueous layer.

EXAMPLE 4 The Preparation of2-(Indole-3-aminomethyl)-2-amidinobenimidazol (Compound 188)

A mixture of 0.035 moles of Indole-3-carboxaldehyde (ICA) (5 g) and2-Guanidino-benzimidazole (GBI) (6 g) in 100–150 ml. of toluene washeated under reflux in a water collector, Dean Stark trap, for as long aperiod as required to collect the theoretical amount of water (12 hours)as follows: the reaction was first stopped after 2 hours and was thenleft to stand overnight at room temperature (25° C.). The next day therefluxing was resumed and carried out for 10 hours in order to collectthe additional water evolving from the reaction of the aldehyde with theamine. After approximately 12 hours, the hot solution was rapidlydecanted in order to remove any insoluble residue. It was thenevaporated to dryness on the steam bath to a crude immine, that waslater crystallized from absolute ethanol.

EXAMPLE 5 The Preparation of 2-(Indole-3-Methylene)-2-hydrazinoimidazole(Compound 52)

A mixture of 0.035 moles each of Indole-3-carboxaldehyde (ICA) (5 g) and2-Hydrazine-2-imidazoline. Hbr (HIM) (6.34 g) in 100–150 ml of toluenewas heated under reflux under a water collector trap (Dean Stark) for aslong a period as required to collect the theoretical amount of water (12hours) as follows: the reaction was first stopped after 2 hours and leftto stand overnight at room temperature (25° C.). The refluxing wasresumed the next day and carried out for 10 hours in order to collectthe additional water evolving from the reaction of the aldehyde with theamine. After approximately 12 hours, the still hot solution was rapidlydecanted in order to remove any insoluble residue. It was thenevaporated to dryness on the steam bath to a crude immine, which waslater crystallized from absolute ethanol.

EXAMPLE 6 The Preparation of Phenylacetamidoamidine (Compound No. 189)Specifics

Phenylacetic acid (PAA) 0.037 mols 5 g) was added to excess SOC1₂ andheated under reflux for 60 minutes at the temperature of 75–80° C. Afterthe reaction was completed, the excess SOC1₂ was eliminated under vacuumevaporation using a water pump (40–50° C.). This process was repeated 2or 3 times, each time adding benzene to aid in SOCl2 elimination. Sincephenylacetylchloride PAC is not volatile (b.p. about 160° C.), SOC12evaporates and PAC remains in the flask. Guanidine (0.018 mole 1.72 g)was shaken with 2N NaOH (2–5 eq.) on an ice bath until it was completelydissolved. Excess NaOH was added either to neutralize HCl evolving fromthe reaction of acyl chloride (PAC) with guanidine or to act as acatalyst in the reaction. PAC was then added very slowly, dropwise, froma funnel with vigorous shaking. After the addition of PAc, the mixturewas stirred at 0° C. for 15–30 minutes. The resulting pale yellowcolored solid was filtered with Whatman #1 filter paper, the pH of thesuspension was determined and adjusted to between 8–8.5, by the additionof dilute HCl, before filtering with the filter paper (W#1). The yellowsolid was recrystallized twice with ethanolic mixture (80% EtOH/H₂O).

EXAMPLE 7 Preparation of 2,4,6-Tris(2,6-dichlorobenzylideneamino)-1,3,5-s-Triazine (Compound No. 18)

A 3:1 ratio mixture of 2.6 dichlorobenzaldehyde and melamine was stirredtogether with a stoichiometric amount of toluene-sulfonic acid as acatalyst, in 150 ml of diglyme as a solvent. The mixture was stirredmanually and then heated under reflux for 17 hours in a Dean Stark watertrap, until the theoretical amount of water was collected. A hotfiltration of the insoluble residue was performed. The hot yellowcolored filtrate was cooled and then evaporated at 100° with a rotaryevaporator under high (2 microns) vacuum. The precipitate was thenrecrystallized twice with a mixed solvent (absolute ethanol and hexane).

Additional Preparations

Following the same procedures as in Examples 1 and 2, additionalcompounds can be prepared by reacting the reagents as shown in Table Ito form the compounds as presented in Table II.

The pharmacologic procedures of the present invention and compositionsfor use in such procedures are illustrated by the following examples.These are intended merely to exemplify the invention and to clarify themethod of operation, without being exclusive of the full scope of thisinvention.

EXAMPLES 8–12

A group of four laboratory rats each weighing approximately 310–350grams were treated by injecting 4 mg guanabenz intraperitoneally, in theform of the acetate salt dissolved in 1 ml of a sterile 5% dextroseaqueous solution. A fifth rat was treated with merely an equal amount ofthe dextrose solution without guanabenz acetate. The rats were subjectedto an electrical tail stimulation, by electrodes attached to theirtails, to determine the point of positive (threshold) vocalization.

The normal vocalization threshold, and the point at which the controlrat vocalized was approximately 7 volts. Beginning seven minutes afterinjection of the guanabenz solution, the four test rats all failed tovocalize after a shock of 10 volts; thereafter, as shown, the animalbecame profoundly anesthetized and no vocalization response was obtainedeven when stimulated at 40 Volts. To bring the rats out of anesthesia,the rats were then injected with 40 mgs. of aminophylline, also in 1 mlof a 5% aqueous dextrose solution. The rat's pain threshold was againtested; as shown, vocalization that was absent during guanabenzanesthesia, returned within 6 minutes after injection of theaminophylline at 12 volts, and then was present at the normal thresholdof 7 volts, by 8 minutes after the injection of aminophylline. Thenormal threshold for vocalization was reestablished, as there was novocalization at 6 volts following recovery from anesthesia.

The rats were maintained under anaesthesia for a period of 50 minutesbefore injection of the aminophylline.

EXAMPLES 13–36

The core temperatures of another twenty test rats were measured: eightrats were injected with guanabenz exactly as in Examples 8–12; anothereight were injected with the same quantity of Compound No. 13 (Melazine)in Tables I and II, also in 5% dextrose solution; and eight rats wereused as a control and injected only with the vehicle, i.e., 5% dextrosesolution. The core temperatures (colonic measurement) of the eightguanabenz-treated test rats dropped from an average normal value of36.5° C. to 22.5° C., and the eight Melazine-treated rats to 21.5° C.,within 25 to 45 minutes, and stabilized at that level. Room temperaturewas 21.5° C. The mean intraperitoneal temperatures of guanabenz- andMelazine-treated rats dropped to 31.5° C. and 30.2° C., respectively, asdid the temperature of their abdominal cavity. The temperatures of theliver and the kidneys each dropped to about 33.5° C. for theguanabenz-treated rats and 32.7° C. for the Melazine-treated rats. Thecontrol rats, injected only with the carrier dextrose solution,maintained a relatively constant temperature during the entire testperiod under identical conditions of the test. The guanabenz-treatedrats were anesthetized, but the Melazine-treated rats remained awake. Aninjection of aminophylline to three of the rats treated with guanabenzcaused them to awaken, but had practically no effect on bodytemperature; injection of the aminophylline to three of themelazine-treated rats had no discernible effect.

Six of the anesthesized rats were also injected with aminophylline, theythen received an injection of tolazoline (an alpha adrenergicantagonist); within 25 minutes the anesthesia-hypothermia induced byguanabenz was completely reversed and the body temperatures of the ratshad returned to normal.

The fourth pair of guanabenz-treated rats were injected I.P. with 10 mgYohimbine in a 5% aqueous dextrose solution. These rats were brought outof anesthesia by yohimbine and their hypothermia was simultaneouslyreversed, rendering the rats awake, with their body temperaturereturning to normal.

EXAMPLES 37–43

Four additional rats were treated with the guanabenz solution as inExamples 8–12, administered intraperitonally. The core temperatures wereagain monitored; they dropped to 21° C. (room temperature).Approximately 30 minutes after receiving the guanabenz injection, therats were placed in a temperature controlled room maintained at minus(−) 30° C. (plus or minus 0.5° C.).

The core temperatures of the four treated rats, as well as that of twocontrol rats who received only the dextrose solution, were continuouslymonitored. It was found that approximately 15 minutes after placementwithin the cold room, the average core temperature of the two controlrats dropped to minus (−) 20° C. At the same time, the core temperaturesof the four rats treated with guanabenz was at approximately plus (+)16° C. Thus, as a further beneficial effect, guanabenz does not producethe usual poikilothermic condition, and, once a reduced temperature isset, in fact, it protects against any dangerous further temperaturedrops or excessive increases, by resetting, the mammals' thermoregulator(thermostat), and thus protecting against extremes of temperaturefluctuations.

EXAMPLES 44–47

A further two rats received, intraperitonally, the same quantity ofguanabenz acetate as in Examples 8–12, at an ambient temperature of 21°C. The core temperatures of the rats were allowed to fall toapproximately 30° C., after about 15 minutes. At that time, the ratswere placed in a temperature controlled room maintained at 42° C.,together with 2 control rats treated only with the dextrose solution.Within three minutes, the control rats expressed extreme agitation andvocalization, and attempted to escape from what appeared to be anuncomfortably hot temperature. The treated rats remained underanesthesia and the core temperatures in each case remained unchanged at30° C.

EXAMPLES 48–59

In the following three sets of experiments, laboratory rats eachweighing 300–350 gins., were injected with guanabenz acetate alone orwith other compounds, to test their effect on core temperature,analgesia, and anesthesia, as determined by evoking several reflexes.

Nos. 28–53: At a room temperature of 21° C., three pairs of rats wereinjected (I.P.) with guanabenz acetate (G, 12 mg/kg) or diazepam (D, 6mg/kg) or a combination (G+D). Twenty minutes after injection, the coretemperature of the G-treated and (G+D)-treated rats was reduced to about31° C. There was no change in the core temperature of the D-treatedrats. The patellar, urethro-anal (bulbocavernosis), startle, and cornealreflexes were absent after 30 minutes in G-treated animals, indicatingprofound anesthesia, but all such reflexes were present in the D-treatedanimals. In the rats treated with the combination of drugs G, and D, theurethro-anal and vestibular reflexes were absent; other reflexes, i.e.,withdrawal, tail compression, corneal, and righting were present,indicating no anesthesia (probably resulting from the inhibition ofc-AMP phosphodiesterase enzyme by the Diazepam, which is similar to theeffect of the xanthines), and thus counteracts the state of anesthesia.

Nos. 54–61: At a room temperature of 19.4° C., each of four pairs ofrats were injected I.P. with either guanabenz acetate (12 mg/kg), orguanabenz acetate (12 mg/kg) plus pentabarbital (25 mg/kg), orpentabarbital alone (25 mg/kg), or ketamine (80 mg/kg), respectively.The mean core temperature of the pairs of rats dropped to 24.3° C.,32.1° C., 29.3° C., and 34.5° C., respectively, one hour afterinjection. All of the reflexes tested in Examples 48–53 had disappearedin all of the animals. Animals receiving guanabenz acetate showedmydriasis, profound exophthalmia and micturition. In the anesthetizedanimals treated with guanabenz acetate, the ears, the forelimb digitsand the hindlimb digits, were pink as compared with the semi-cyanoticappearance of the ears and digits of the animals treated withpentabarbital and ketamine that did not survive the given doses of thedrugs.

EXAMPLES 62

A 70 kg mammal is administered 6 mg guanabenz dissolved in 1 ml ofsterile 5% dextrose aqueous solution, administered by intravenousinjection over a period of three minutes. After exhibiting deepsedation, within five minutes after injection, the mammal falls intoprofound anesthesia. The large mammal does not overtly react to thenoxious stimulation of pin-pricks at its upper extremity (digits), anddoes not exhibit the corneal reflex.

An intravenous drip of 5% aqueous dextrose solution containing 0.1 mgguanabenz/ml is administered beginning about 120 minutes after theinitial injection, at a constant rate of 1 ml/min, over an additionalperiod of 30 minutes. The large mammal continues under profoundanesthesia for an additional about two hours. Thereafter, an intravenousinjection containing 20 mg of aminophylline is administered over aperiod of five minutes. The large mammal is fully awakened within about20 minutes, appearing alert and refreshed.

The period of time required to fully reverse the anesthesia can beincreased or decreased by proportionally changing the amount of theantagonist. After metabolism of guanabenz, the mammal will spontaneouslyawaken, within about three to six hours after the I.V. drip isdiscontinued.

EXAMPLES 63–66

Examples 8–12 are repeated except that an equal dosage bolus (4 mg) oftolazoline in dextrose solution is intravenously administeredapproximately twenty minutes before commencing the first bolus injectionof the guanabenz acetate.

The four Sprague-Dawley rats become anesthetized within five minutes,and remain under anesthesia for as long as four hours without furtheradministration of the guanabenz.

EXAMPLES 67–70

Two rats received, intraperitonally, the same quantity as in Examples8–12 of Compound No. 18, the acetate salt of2,4–6-Tris-(2,6-dichlorobenzylideneamino)-1,3,5-s-triazine, at anambient temperature of 21° C. The core temperatures of the rats wereallowed to fall to approximately 30° C. At that time, the rats wereplaced in a temperature controlled room maintained at 42° C., togetherwith two control rats treated only with the dextrose solution. Withintwo minutes, the control rats expressed extreme agitation andvocalization, and attempted to escape from what appeared to be anuncomfortably hot temperature. The treated rats remained calm, butactive, and the core temperatures of each treated rat remained unchangedat 30° C.

EXAMPLES 71–86

Efficacy of the treatment with compounds of this invention very lowambient temperatures is demonstrated by the following examples:

Sprague-Dawley rats (8) were injected, IP, with 12 mg/kg each ofguanabenz in 5% aqueous dextrose solution and eight other rats wereinjected with the carrier solution only. All sixteen rats were placed ina temperature-controlled room maintained at 4°–5° d. immediately afterinjection. The brain temperatures of all 16 rats were recorded after 45minutes: the control rats maintained a substantially constant averagebrain temperature of approximately 36.7° C., the brain temperature ofthe guanabenz-treated rats dropped from the original mean of 37° C. to amean of 27° C. The colonic, or core, temperature of the eightguanabenz-treated rats was measured after 15, 20, 28, 37, 40 and 45minutes. The temperature was found to have dropped to approximately 24°C. after 15 minutes, to 22° C. after 22 minutes, to 20° C. after 30minutes, and down to 17° C. after 45 minutes. The core temperature hadits major drop during the initial 15 to 20 minutes time period.Ultimately, the core temperature reached a value of 10° C. lower thanthe brain temperature. Mammals treated with the guanidino compoundspossessing hypothermic properties are protected from extreme temperaturefluctuations. They resume normal behavior after this experiment, i.e.,drinking, eating and grooming, etc.

It is of interest to note that some of the same neuroprotectivecompounds which provide relief from the effects of severe trauma orother injuries to the central nervous system, can also serve aseffective anesthetic agents during surgical procedures. For example, foran accident victim that has suffered severe spinal injury, the samecompound, e.g., guanabenz, can provide anesthesia as well asneuroprotection. It is thus possible, under, e.g., guanabenz anesthesia,to provide the surgical treatment necessary to correct any mechanicaleffects of the accident, i.e., removing any bone compression or bonefragments, while simultaneously starting the medical treatment of theindividual, using the same anesthetic compound.

Chronically injured mammals can also be successfully treated utilizingthe compounds and procedures of this invention. The following comprise auseful method for functional restoration:

All animal species admitted with traumatic spinal cord injury willreceive high quality nursing care. The paralyzed animals will beexamined by x-ray, cat scan or MRI. It is preferable to use both of thelatter procedures to localize the area of the injury and determine ifthe compromised spinal cord is in need of decompression. All necessaryneurosurgical procedures should be performed to correct and remove anyadhesions or compression of the spinal cord. For any such operation,guanabenz (12 mg/kg) should be used as an anesthesia.

During the laminectomy surgery, after the dura has been exposed, if scartissue has formed, the area of the scar at the lesion site can be frozenby liquid nitrogen using an instrument (formed of a steel bowl attachedto a tube 18 cm long, 0.8 cm diameter, with a concave surface at the endand containing a hole 1 mm in diameter, in the middle, through whichliquid nitrogen drips onto the scar). After 5 minutes of freezing thescar tissue, the animals are then resutured. Alternatively, collagenasealone or with streptokinase, can be applied to the scar tissue. It isalso useful to apply both liquid nitrogen and collagenase.

If the neuroradiological methods demonstrate no compression of thespinal cord, laminectomy is unnecessary. However, the scar tissue shouldstill be softened. The area of the scar can be localizedfluoroscopically, and preferably collegenase (and possiblystreptokinase) is directed to the area of the lesion obviating the needfor performing the laminectomy.

The animals are treated with a guanidino compound, e.g., guanphylline oraminoguanphylline, twice daily (1 mg/kg). Approximately 10, 14 and 20days after treatment with, e.g., guanphylline or aminoguanphylline iscommenced, these animals can also be treated with a serotonergic(“5-HT”) receptor agonist; such as quipazine (1–2 mg/kg). Suchserotonergic compounds can accelerate the recovery period, i.e., shortenthe period after which time the animals become mobile. The animalsshould then continue to be treated systemically with the guanidinocompound twice daily for six to eight weeks, or until functionalrecovery has been achieved.

Many rats and cats have been treated with several alpha-adrenoceptoragonists in order to ascertain which drug has the least side effects andreduces the time period for recovery. Aminoguanphylline, guanphylline,7-(guanidinoacetyl)-theophylline have been found efficacious.

The purpose of liquid nitrogen is to reduce the structural integrity ofthe collagen laden, glial scar tissue, by freezing and defrosting.Collagenase then initiates a debridgement of the scar without attackingthe nervous and osseous tissue. If required, streptokinase, oralteplase, both plasminogen activators can also be used to bring about acomplete debridgement. In addition to 3-amino-propionitrile (alatherogen), 5-fluorodeoxyuridine and dehydroproline can be used toarrest further glial and fibroblastic invasion of the scar region,respectively. Aminoguanidine, aminoguanphylline, clonidine, guanabenz,and guanphylline also interfere with formation of the scar.

Maintaining treatment for several months is needed for primates.

We have found that subjecting the animals to other physiologicalmanipulations and exercise is effective in the recovery process, e.g.,the use of treadmill, retrograde (sciatic nerve) stimulation, andfunctional electrical stimulation.

1. Pharmacologically active compositions having the capability ofimproving the neurological health of a mammal, the compositionscomprising a unit dosage amount of a guanidino compound having at leasttwo neurologically active receptor groups, one such neurologicallyactive receptor group providing alpha-adrenergic agonist activity and asecond such neurologically active receptor group providing dopaminergicagonist activity, the alpha-adrenergic agonist activity further beingprovided by at least one guanidino group and the dopaminergic agonistactivity being provided by at least one 3,4-disubstituted phenyl group,each such phenyl substituent being negatively charged and being selectedfrom the group consisting of hydroxyl groups and halogen atoms, and theguanidino compound being sufficiently lipophilic to be capable ofcrossing the blood/central nervous system barrier, and a physiologicallysuitable carrier, wherein the the guanidino compound is selected fromthe group consisting of:2-(Amino)-4-(2,6-dichlorobenzylideneamino)-6-(3,4-dihydroxyphenyl-7-(S)-hydroxyethyleneamino)1,3,5-s-Triazine;2,4-Bis-(2,6-dichlorobenzylideneamino)-6-(3,4-dihydroxyphenylethylamino)-1,3,5-s-triazine;2-(2,6-Dichlorobenzylideneamino)-4-(3,4-dihydroxyphenylethylamino)-6-(5-hydroxyindole-ethylamino)-1,3,5-s-triazine;N-(2,6-Dichlorobenzylideneguanidino)-2-(3,4-dihydroxyphenyl)-2-(S)-hydroxyethylimine;3,4-Dihydroxyphenylethylene aminoguanidine;3-(3,4-Dichlorophenoxy)-benzylidene aminoguanidine;3,4-Dichlorophenylethylaminoguanidine;N-(6-Hydroxy-2,5,7,8-tetramethylchroman-2-carbonyl)N′-(3,4-dihydroxyphenyl)-2-(S)-hydroxyethylguanidine;and3-(3,4-Dihydroxyphenyl)-2-(S)-(2,6-dichlorbenzylideneamino)-N-guanidinopropionamide.2. The compound2-(2,6-Dichlorobenzylideneamino)-4-(3,4-dihydroxyphenylethylamino)-6-(5-hydroxyindole-3-ethylamino)-1,3,5-s-triazine.3. Compounds having the formula 2-(X)-4(Y)-6-(Z)-1,3,5-s-triazine,wherein each of X, Y and Z is selected from the group consisting ofDihalobenzylideneamino groups; dihydroxyphenylethylamino groups; and5-hydroxyindole-3-ethylamino groups; wherein one member of each group ispresent in each compound.